Fused heterotricyclic organic compounds, pharmaceutical compositions, and medical uses thereof

ABSTRACT

The invention provides fused heterocyclic organic compounds such as dihydropyrazolopyridotriazinones, compositions containing such compounds, medical kits, and methods for using such compounds and compositions for body contouring and/or reduction of fat in a subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/126,126, filed Dec. 18, 2020, which is a divisional of U.S. patentapplication Ser. No. 16/048,603, filed Jul. 30, 2018, now U.S. Pat. No.10,888,563, which is a divisional of U.S. patent application Ser. No.15/133,533, filed Apr. 20, 2016, now U.S. Pat. No. 10,058,553, which isa continuation of International Patent Application numberPCT/US2014/061517 filed Oct. 21, 2014, which claims the benefit of andpriority to U.S. Provisional Patent Application Ser. No. 61/893,529,filed Oct. 21, 2013; U.S. Provisional Patent Application Ser. No.61/893,544, filed Oct. 21, 2013; U.S. Provisional Patent ApplicationSer. No. 61/893,556, filed Oct. 21, 2013; and U.S. Provisional PatentApplication Ser. No. 61/893,564, filed Oct. 21, 2013; the contents ofeach of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention provides fused heterocyclic organic compounds such asdihydropyrazolopyridotriazinones, compositions containing suchcompounds, medical kits, and methods for using such compounds andcompositions for body contouring and/or reduction of fat in a subject.

BACKGROUND

Adipose tissue is composed mostly of adipocyte cells (i.e., fat cells),and the primary role of adipose tissue is the storage of energy in theform of lipids (e.g., triglycerides). Excessive amounts of adiposetissue in a subject can lead to disorders such as type 2 diabetes,inflammatory diseases, and cancer. Additionally, adipose tissue (i.e.,body fat) can accumulate unevenly in the body and lead to undesirablefatty deposits. The energy stored in body fat can be utilized bybreaking down the triglycerides in the body fat to liberate fatty acidsthrough a process referred to as lipolysis. However, utilization of bodyfat may occur unevenly and the accumulation of fatty deposits inparticular regions of the body can be cosmetically unappealing.

There are various reports in the literature of compositions used toreduce the amount of adipose tissue in a subject. Certain reportscharacterize the compositions as slimming agents for use in reducing theamount of adipose tissue in a particular area of the subject's body,such as the face or neck. For example, U.S. Pat. No. 8,513,310 isgenerally directed to cosmetic uses of phytosphingosine and cosmeticcompositions containing this compound for use as a slimming agent. U.S.Patent Application Publication No. 2008/058287 is generally directed toa mesotherapy cream. U.S. Patent Application Publication No. 2010/063006is generally directed to compositions and methods to reduce fat andretract skin. Also, U.S. Patent Application Publication No. 2011/218163is generally directed to paeoniflorin preparations and uses thereof forfat reduction.

However, despite the progress reported in the literature for developingcompositions that may be used as medicinal agents to reduce theaccumulation of fat in a particular area of a subject's body, the needremains for compositions with improved ability to reduce theaccumulation of fat in particular areas of a subject's body. The presentinvention addresses this need and provides other related advantages.

SUMMARY

The invention provides fused heterocyclic organic compounds such asdihydropyrazolopyridotriazinones, compositions containing suchcompounds, medical kits, and methods for using such compounds andcompositions for body contouring and/or reduction of fat in a subject.The compounds and compositions can be used to reduce the amount oflocalized deposits of subcutaneous fat in a subject, such assubcutaneous deposits of fat in the vicinity of the subject's face,neck, chin, submental region, arm, stomach, or other body part. Thecompounds and compositions can also be used to treat medical disordersassociated with local accumulation of fat, such as an adipose tissuetumor (e.g., a lipoma), fat embolism, or fatty liver disease.Pharmaceutical compositions, particularly injectable pharmaceuticalcompositions suited for cosmetic procedures, are provided. Variousaspects of the invention are provided in more detail below.

One aspect of the invention provides a family of fused heterotricyclicorganic compounds embraced by Formula I in Section II herein that may beused in the methods, compositions and kits described herein, whereinFormula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a cosmetic method of modifyingthe contour of a subject's externally exposed body part containing fat.The method comprises administering to said body part an amount of afused heterotricyclic organic compound described herein, such as acompound of Formula I in Section II herein, effective to modify thecontour of said body part.

Another aspect of the invention provides a method of reducing the amountof subcutaneous fat in a subject. The method comprises exposingsubcutaneous fat in a subject to an effective amount of a fusedheterotricyclic organic compound described herein, such as a compound ofFormula I in Section II herein, to reduce the amount of subcutaneous fatin said subject.

Another aspect of the invention provides a method for inducingretraction of dermal tissue in a subject. The method comprisesadministering an effective amount of a fused heterotricyclic organiccompound described herein, such as a compound of Formula I in Section IIherein, to dermal tissue of a subject to induce retraction of dermaltissue.

Another aspect of the invention provides a method for inducingretraction of subcutaneous tissue in a subject. The method comprisesadministering an effective amount of a fused heterotricyclic organiccompound described herein, such as a compound of Formula I in Section IIherein, to subcutaneous tissue of a subject to induce retraction ofsubcutaneous tissue.

Another aspect of the invention provides a method of preventing theaccumulation of fat in a subject. The method comprises administering toa subject in need thereof an effective amount of a fused heterotricyclicorganic compound described herein, such as a compound of Formula I inSection II herein, to prevent accumulation of fat in the subject.

Another aspect of the invention provides a method of treating a disorderselected from the group consisting of an adipose tissue tumor, fatembolism, dyslipidemia, or fatty liver disease in a subject. The methodcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a fused heterotricyclic organic compound describedherein, such as a compound of Formula I in Section II herein, to treatthe disorder.

Another aspect of the invention provides a method of reducing the amountof fat or cholesterol in a subject. The method comprises administeringto a subject in need thereof an effective amount of a fusedheterotricyclic organic compound described herein, such as a compound ofFormula I in Section II herein, to reduce the amount of fat orcholesterol in the subject.

Another aspect of the invention provides a method of reducing the amountof mesenchymal pre-adipocyte stem cell precursors in a subject. Themethod comprises administering to a subject in need thereof an effectiveamount of a fused heterotricyclic organic compound described herein,such as a compound of Formula I in Section II herein, to reduce theamount of mesenchymal pre-adipocyte stem cell precursors in the subject.

Another aspect of the invention provides a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and a fusedheterotricyclic organic compound described herein, such as a compound ofFormula I in Section II herein.

Another aspect of the invention provides a family ofdipyrido-pyrimidinone organic compounds embraced by Formula I in SectionIII herein that may be used in the methods, compositions and kitsdescribed herein, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a cosmetic method of modifyingthe contour of a subject's externally exposed body part containing fat.The method comprises administering to said body part an amount of adipyrido-pyrimidinone organic compound described herein, such as acompound of Formula I in Section III herein, effective to modify thecontour of said body part.

Another aspect of the invention provides a method of reducing the amountof subcutaneous fat in a subject. The method comprises exposingsubcutaneous fat in a subject to an effective amount of adipyrido-pyrimidinone organic compound described herein, such as acompound of Formula I in Section III herein, to reduce the amount ofsubcutaneous fat in said subject.

Another aspect of the invention provides a method for inducingretraction of dermal tissue in a subject. The method comprisesadministering an effective amount of a dipyrido-pyrimidinone organiccompound described herein, such as a compound of Formula I in SectionIII herein, to dermal tissue of a subject to induce retraction of dermaltissue.

Another aspect of the invention provides a method for inducingretraction of subcutaneous tissue in a subject. The method comprisesadministering an effective amount of a dipyrido-pyrimidinone organiccompound described herein, such as a compound of Formula I in SectionIII herein, to subcutaneous tissue of a subject to induce retraction ofsubcutaneous tissue.

Another aspect of the invention provides a method of preventing theaccumulation of fat in a subject. The method comprises administering toa subject in need thereof an effective amount of a dipyrido-pyrimidinoneorganic compound described herein, such as a compound of Formula I inSection III herein, to prevent accumulation of fat in the subject.

Another aspect of the invention provides a method of treating a disorderselected from the group consisting of an adipose tissue tumor, fatembolism, dyslipidemia, or fatty liver disease in a subject. The methodcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a dipyrido-pyrimidinone organic compound describedherein, such as a compound of Formula I in Section III herein, to treatthe disorder.

Another aspect of the invention provides a method of reducing the amountof fat or cholesterol in a subject. The method comprises administeringto a subject in need thereof an effective amount of adipyrido-pyrimidinone organic compound described herein, such as acompound of Formula I in Section III herein, to reduce the amount of fator cholesterol in the subject.

Another aspect of the invention provides a method of reducing the amountof mesenchymal pre-adipocyte stem cell precursors in a subject. Themethod comprises administering to a subject in need thereof an effectiveamount of a dipyrido-pyrimidinone organic compound described herein,such as a compound of Formula I in Section III herein, to reduce theamount of mesenchymal pre-adipocyte stem cell precursors in the subject.

Another aspect of the invention provides a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and adipyrido-pyrimidinone organic compound described herein, such as acompound of Formula I in Section III herein.

Another aspect of the invention provides a family oftetrahydropyrimido-furo-isoquinolinone organic compounds embraced byFormula I in Section IV herein that may be used in the methods,compositions and kits described herein, wherein Formula I is representedby:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a cosmetic method of modifyingthe contour of a subject's externally exposed body part containing fat.The method comprises administering to said body part an amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I in Section IV herein, effectiveto modify the contour of said body part.

Another aspect of the invention provides a method of reducing the amountof subcutaneous fat in a subject. The method comprises exposingsubcutaneous fat in a subject to an effective amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I in Section IV herein, to reducethe amount of subcutaneous fat in said subject.

Another aspect of the invention provides a method for inducingretraction of dermal tissue in a subject. The method comprisesadministering an effective amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I in Section IV herein, to dermaltissue of a subject to induce retraction of dermal tissue.

Another aspect of the invention provides a method for inducingretraction of subcutaneous tissue in a subject. The method comprisesadministering an effective amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I in Section IV herein, tosubcutaneous tissue of a subject to induce retraction of subcutaneoustissue.

Another aspect of the invention provides a method of preventing theaccumulation of fat in a subject. The method comprises administering toa subject in need thereof an effective amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I in Section IV herein, to preventaccumulation of fat in the subject.

Another aspect of the invention provides a method of treating a disorderselected from the group consisting of an adipose tissue tumor, fatembolism, dyslipidemia, or fatty liver disease in a subject. The methodcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a tetrahydropyrimido-furo-isoquinolinone organiccompound described herein, such as a compound of Formula I in Section IVherein, to treat the disorder.

Another aspect of the invention provides a method of reducing the amountof fat or cholesterol in a subject. The method comprises administeringto a subject in need thereof an effective amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I in Section IV herein, to reducethe amount of fat or cholesterol in the subject.

Another aspect of the invention provides a method of reducing the amountof mesenchymal pre-adipocyte stem cell precursors in a subject. Themethod comprises administering to a subject in need thereof an effectiveamount of a tetrahydropyrimido-furo-isoquinolinone organic compounddescribed herein, such as a compound of Formula I in Section IV herein,to reduce the amount of mesenchymal pre-adipocyte stem cell precursorsin the subject.

Another aspect of the invention provides a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I in Section IV herein.

Another aspect of the invention provides a family oftetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compounds embraced byFormula I in Section V herein that may be used in the methods,compositions and kits described herein, wherein Formula I is representedby:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a cosmetic method of modifyingthe contour of a subject's externally exposed body part containing fat.The method comprises administering to said body part an amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I in Section V herein, effectiveto modify the contour of said body part.

Another aspect of the invention provides a method of reducing the amountof subcutaneous fat in a subject. The method comprises exposingsubcutaneous fat in a subject to an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I in Section V herein, to reducethe amount of subcutaneous fat in said subject.

Another aspect of the invention provides a method for inducingretraction of dermal tissue in a subject. The method comprisesadministering an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I in Section V herein, to dermaltissue of a subject to induce retraction of dermal tissue.

Another aspect of the invention provides a method for inducingretraction of subcutaneous tissue in a subject. The method comprisesadministering an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I in Section V herein, tosubcutaneous tissue of a subject to induce retraction of subcutaneoustissue.

Another aspect of the invention provides a method of preventing theaccumulation of fat in a subject. The method comprises administering toa subject in need thereof an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I in Section V herein, to preventaccumulation of fat in the subject.

Another aspect of the invention provides a method of treating a disorderselected from the group consisting of an adipose tissue tumor, fatembolism, dyslipidemia, or fatty liver disease in a subject. The methodcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organiccompound described herein, such as a compound of Formula I in Section Vherein, to treat the disorder.

Another aspect of the invention provides a method of reducing the amountof fat or cholesterol in a subject. The method comprises administeringto a subject in need thereof an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I in Section V herein, to reducethe amount of fat or cholesterol in the subject.

Another aspect of the invention provides a method of reducing the amountof mesenchymal pre-adipocyte stem cell precursors in a subject. Themethod comprises administering to a subject in need thereof an effectiveamount of a tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compounddescribed herein, such as a compound of Formula I in Section V herein,to reduce the amount of mesenchymal pre-adipocyte stem cell precursorsin the subject.

Another aspect of the invention provides a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I in Section V herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a histogram profile showing ethidium homodimer fluorescenceintensity when adipocytes are incubated with 10 mg/mL of test compoundor control for 1 hr, 3 hrs, or overnight, as described in Example 1;

FIG. 2 is an expanded view of the histogram profile showing ethidiumhomodimer fluorescence intensity when adipocytes are incubated with 10mg/mL of test compound or control for 1 hr, 3 hrs, or overnight, asdescribed in Example 1.

FIG. 3 is a histogram profile showing ethidium homodimer fluorescenceintensity when adipocytes are incubated with 10 mg/mL of test compoundor control for 1 hr, 4 hrs, 18 hrs, or 24 hrs, as described in Example2; and

FIG. 4 is a histogram profile showing ethidium homodimer fluorescenceintensity when adipocytes are incubated with 15 mg/mL of test compoundor control for 1 hr, 3 hrs, or overnight, as described in Example 2.

FIG. 5 is a histogram profile showing ethidium homodimer fluorescenceintensity when adipocytes are incubated with 10 mg/mL of test compoundor control for 1 hr, 3 hrs, or overnight, as described in Example 3.

FIG. 6 is a histogram profile showing ethidium homodimer fluorescenceintensity when adipocytes are incubated with 10 mg/mL of test compoundor control for 1 hr, 3 hrs, or overnight, as described in Example 4.

DETAILED DESCRIPTION

The invention provides fused heterocyclic organic compounds such asdihydropyrazolopyridotriazinones, compositions containing suchcompounds, medical kits, and methods for using such compounds andcompositions for body contouring and/or reduction of fat in a subject.The compounds and compositions can be used to reduce the amount oflocalized deposits of subcutaneous fat in a subject, such assubcutaneous deposits of fat in the vicinity of the subject's face,neck, chin, submental region, arm, stomach, or other body part. Thecompounds and compositions can also be used to treat medical disordersassociated with local accumulations of fat, such as an adipose tissuetumor (e.g., a lipoma), fat embolism, or fatty liver disease.Pharmaceutical compositions, particularly injectable pharmaceuticalcompositions suited for cosmetic procedures, are provided. The practiceof the present invention employs, unless otherwise indicated,conventional techniques of organic chemistry, pharmacology, cellbiology, and biochemistry. Such techniques are explained in theliterature, such as in “Comprehensive Organic Synthesis” (B. M. Trost &I. Fleming, eds., 1991-1992); “Current protocols in molecular biology”(F. M. Ausubel et al., eds., 1987, and periodic updates); and “Currentprotocols in immunology” (J. E. Coligan et al., eds., 1991), each ofwhich is herein incorporated by reference in its entirety. Variousaspects of the invention are set forth below in sections; however,aspects of the invention described in one particular section are not tobe limited to any particular section.

I. Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂alkyl,C₁-C₁₀alkyl, and C₁-C₆alkyl, respectively. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

The term “alkylene” refers to a diradical of an alkyl group. Anexemplary alkylene group is —CH₂CH₂—.

The term “haloalkyl” refers to an alkyl group that is substituted withat least one halogen. For example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃,and the like.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic,or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8,or 4-6 carbons, referred to herein, e.g., as “C₄₋₈cycloalkyl,” derivedfrom a cycloalkane. Exemplary cycloalkyl groups include, but are notlimited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.Unless specified otherwise, cycloalkyl groups are optionally substitutedat one or more ring positions with halogen, alkoxy, or alkyl. In certainembodiments, the cycloalkyl group is not substituted, i.e., it isunsubstituted.

The term “cycloalkylene” refers to a diradical of an cycloalkyl group.An exemplary cycloalkylene group is

The term “aryl” is art-recognized and refers to a carbocyclic aromaticgroup. Representative aryl groups include phenyl, naphthyl, anthracenyl,and the like. Unless specified otherwise, the aromatic ring may besubstituted at one or more ring positions with, for example, halogen,azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl,amino, nitro, sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl,—CO₂alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido,sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroarylmoieties, —CF₃, —CN, or the like. The term “aryl” also includespolycyclic ring systems having two or more carbocyclic rings in whichtwo or more carbons are common to two adjoining rings (the rings are“fused rings”) wherein at least one of the rings is aromatic, e.g., theother cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls,and/or aryls. In certain embodiments, the aromatic ring is substitutedat one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl.In certain other embodiments, the aromatic ring is not substituted,i.e., it is unsubstituted.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup.

The term “heteroaryl” is art-recognized and refers to aromatic groupsthat include at least one ring heteroatom. In certain instances, aheteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representativeexamples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl,pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Unless specifiedotherwise, the heteroaryl ring may be substituted at one or more ringpositions with, for example, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino,amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl,alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like. Theterm “heteroaryl” also includes polycyclic ring systems having two ormore rings in which two or more carbons are common to two adjoiningrings (the rings are “fused rings”) wherein at least one of the rings isheteroaromatic, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, and/or aryls. In certain embodiments, theheteroaryl ring is substituted at one or more ring positions withhalogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, theheteroaryl ring is not substituted, i.e., it is unsubstituted.

The term “heteroaralkyl” refers to an alkyl group substituted with aheteroaryl group.

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl” and “heterocyclic group” are art-recognized andrefer to saturated or partially unsaturated 3- to 10-membered ringstructures, alternatively 3- to 7-membered rings, whose ring structuresinclude one to four heteroatoms, such as nitrogen, oxygen, and sulfur.The number of ring atoms in the heterocyclyl group can be specifiedusing C_(x)-C_(x) nomenclature where x is an integer specifying thenumber of ring atoms. For example, a C₃-C₇heterocyclyl group refers to asaturated or partially unsaturated 3- to 7-membered ring structurecontaining one to four heteroatoms, such as nitrogen, oxygen, andsulfur. The designation “C₃-C₇” indicates that the heterocyclic ringcontains a total of from 3 to 7 ring atoms, inclusive of any heteroatomsthat occupy a ring atom position. One example of a C₃heterocyclyl isaziridinyl. Heterocycles may also be mono-, bi-, or other multi-cyclicring systems. A heterocycle may be fused to one or more aryl, partiallyunsaturated, or saturated rings. Heterocyclyl groups include, forexample, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl,dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl,imidazolidinyl, isoquinolyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl,piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl,tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl,thiazolidinyl, thiolanyl, thiomorpholinyl, thiopyranyl, xanthenyl,lactones, lactams such as azetidinones and pyrrolidinones, sultams,sultones, and the like. Unless specified otherwise, the heterocyclicring is optionally substituted at one or more positions withsubstituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido,amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy,cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato,phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.In certain embodiments, the heterocyclcyl group is not substituted,i.e., it is unsubstituted.

The term “heterocycloalkyl” is art-recognized and refers to a saturatedheterocyclyl group as defined above.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety represented by thegeneral formula —N(R⁵⁰)(R⁵¹), wherein R⁵⁰ and R⁵¹ each independentlyrepresent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl,aralkyl, or —(CH₂)_(m)—R⁶¹; or R⁵⁰ and R⁵¹, taken together with the Natom to which they are attached complete a heterocycle having from 4 to8 atoms in the ring structure; R⁶¹ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8. In certain embodiments, R⁵⁰ and R⁵¹ eachindependently represent hydrogen, alkyl, alkenyl, or —(CH₂)_(m)—R⁶¹.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,—O—(CH₂)_(m)—R₆₁, where m and R₆₁ are described above.

The term “carbamate” as used herein refers to a radical of the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i—), or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h) and R_(i) are each independently alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, sulfide, sulfonyl, orsulfonamide. Exemplary carbamates include arylcarbamates and heteroarylcarbamates, e.g., wherein at least one of R_(g), R_(h) and R_(i) areindependently aryl or heteroaryl, such as phenyl and pyridinyl.

The term “amide” or “amido” as used herein refers to a radical of theform —R_(a)C(O)N(R_(b))—, —R_(a)C(O)N(R_(b))R_(c)—, —C(O)NR_(b)R_(c), or—C(O)NH₂, wherein R_(a), R_(b) and R_(c) are each independently alkoxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, or nitro. The amide can beattached to another group through the carbon, the nitrogen, R_(b),R_(c), or R_(a). The amide also may be cyclic, for example R_(b) andR_(c), R_(a) and R_(b), or R_(a) and R_(c) may be joined to form a 3- to12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-memberedring.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C₂-C₁₂alkenyl, C₂-C₁₀alkenyl, and C₂-C₆alkenyl,respectively. Exemplary alkenyl groups include vinyl, allyl, butenyl,pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, and the like.

The term “sulfonamide” or “sulfonamido” as used herein refers to aradical having the structure —N(R_(r))—S(O)₂—R_(s)— or—S(O)₂—N(R_(r))R_(s), where R_(r), and R_(s) can be, for example,hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl. Exemplarysulfonamides include alkylsulfonamides (e.g., where R_(s) is alkyl),arylsulfonamides (e.g., where R_(s) is aryl), cycloalkyl sulfonamides(e.g., where R_(s) is cycloalkyl), and heterocyclyl sulfonamides (e.g.,where R_(s) is heterocyclyl), etc.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly. It is understood that graphical depictions ofchemical structures, e.g., generic chemical structures, encompass allstereoisomeric forms of the specified compounds, unless indicatedotherwise.

Individual stereoisomers of compounds of the present invention can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Stereoisomers can also be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentinvention. The symbol

denotes a bond that may be a single, double or triple bond as describedherein. The present invention encompasses the various geometric isomersand mixtures thereof resulting from the arrangement of substituentsaround a carbon-carbon double bond or arrangement of substituents arounda carbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The invention also encompasses isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed herein by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

The invention also encompasses solvates of compounds described herein.“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

As used herein, the terms “subject” and “patient” refer to organisms tobe treated by the methods of the present invention. Such organisms arepreferably mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and more preferably humans.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see, e.g., Martin,Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton,Pa. [1975].

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metal (e.g.,sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

II. Fused Heterotricyclic Organic Compounds & Their Use

Certain aspects of the invention provide fused heterotricyclic organiccompounds, pharmaceutical compositions containing such compounds,medical kits, and therapeutic applications using such compounds. Thesecompounds, pharmaceutical compositions, medical kits, and therapeuticapplications are described in more detail in the sections below.

A. Fused Heterotricyclic Organic Compounds

One aspect of the invention provides fused heterotricyclic organiccompounds such as dihydropyrazolopyridotriazinones. The fusedheterotricyclic organic compounds are contemplated to be useful in themethods, compositions, and kits described herein. In certainembodiments, the fused heterotricyclic organic compound is a compoundembraced by Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

R¹ is —(C₁-C₆)alkylene-X¹, —(C₃-C₆)cycloalkyl-X¹, —CO₂R⁶, —C(O)R⁶, —OH,or —N(R⁶)C(O)—(C₁-C₆)alkyl;

X¹ is —CO₂R⁶, —C(O)R⁶, —C(O)N(R⁷)R⁶, —N(R⁷)C(O)R⁶, or —OR⁶;

R² and R³ each represent independently hydrogen or —(C₁-C₆)alkyl;

R⁴ is hydrogen, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkoxy, or—(C₃-C₇)cycloalkoxy;

R⁵ is phenyl, 5-6 membered heteroaryl, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkoxy, or aralkyl, each of which is optionally substituted with1, 2, or 3 substituents independently selected from the group consistingof halogen, —(C₁-C₆)alkyl, —(C₃-C₅)cycloalkyl, hydroxyl, and—(C₁-C₆)alkoxy; or R₅ is hydrogen or —(C₁-C₆)alkyl; and

R⁶ and R⁷ each represent independently hydrogen or —(C₁-C₆)alkyl.

In certain embodiments, R¹ is —(C₁-C₆)alkylene-X¹ or—(C₃-C₆)cycloalkyl-X¹. In certain other embodiments, R¹ is—(C₁-C₆)alkylene-X¹. In certain other embodiments, R¹ is—(C₁-C₆)alkylene-CO₂R⁶. In certain other embodiments, R¹ is—(CH₂)₂—CO₂R⁶. In certain other embodiments, R¹ is—(C₁-C₆)alkylene-CO₂H. In certain other embodiments, R¹ is —(CH₂)₂—CO₂H.In certain other embodiments, R¹ is —(CH₂)₃—OCH₃.

In certain embodiments, X¹ is —CO₂R⁶ or —C(O)R⁶. In certain otherembodiments, X¹ is —CO₂R⁶.

In certain embodiments, R² and R³ are hydrogen.

In certain embodiments, R⁴ —(C₁-C₆)alkyl. In certain other embodiments,R⁴ is methyl or ethyl. In certain other embodiments, R⁴ is hydrogen.

In certain embodiments, R⁵ is phenyl or a 5-6 membered heteroaryl, eachof which is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen and—(C₁-C₆)alkyl. In certain other embodiments, R⁵ is phenyl optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen and —(C₁-C₆)alkyl. In certain otherembodiments, R⁵ is phenyl substituted with chloro, bromo, or fluoro. Incertain embodiments, R⁵ is phenyl substituted at the para-position withchloro or fluoro. In certain other embodiments, R⁵ is phenyl. In certainembodiments, R₅ is —(C₁-C₆)alkyl.

The description above describes multiple embodiments relating tocompounds of Formula I. The patent application specifically contemplatesall combinations of the embodiments. For example, the inventioncontemplates a compound of Formula I wherein R¹ is —(C₁-C₆)alkylene-X¹,X¹ is —CO₂R⁶, R² and R³ are hydrogen, and R⁵ is phenyl optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen and —(C₁-C₆)alkyl.

In certain embodiments, the compound is a compound of Formula I-A:

or a pharmaceutically acceptable salt thereof; wherein:

R^(1A) is —(C₁-C₆)alkylene-CO₂R^(6A), —(C₃-C₆)cycloalkyl-CO₂R^(6A),—(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl-O—(C₁-C₆)alkyl;

R^(2A) and R^(3A) each represent independently hydrogen or methyl;

R_(4A) is hydrogen or —(C₁-C₆)alkyl;

R^(5A) represents independently for each occurrence hydrogen, halogen,or —(C₁-C₆)alkyl;

R_(6A) is hydrogen or —(C₁-C₆)alkyl, and

n is 1, 2, or 3.

In certain embodiments, R^(1A) is —(C₁-C₆)alkylene-CO₂R^(6A). In certainembodiments, R^(2A) and R^(3A) are hydrogen. In certain embodiments,R^(6A) is hydrogen. In certain embodiments, n is 1.

The description above describes multiple embodiments relating tocompounds of Formula I-A. The patent application specificallycontemplates all combinations of the embodiments.

In certain embodiments, the compound is one of the following or apharmaceutically acceptable salt thereof:

In certain other embodiments, the compound is one of the following or apharmaceutically acceptable salt thereof:

In certain other embodiments, the compound is one of the compoundslisted in Table 1 below or a pharmaceutically acceptable salt thereof.

TABLE 1

Compound No. R¹ R² R³ R⁴ R⁵ I-1 —(CH₂)CO₂H H H H phenyl I-2 —(CH₂)₂CO₂NaH H methyl phenyl I-3 —(CH₂)₂CO₂H H H ethyl phenyl I-4 —(CH₂)₂CO₂H H Hethyl para-chloro-phenyl I-5 —(CH₂)₂CO₂H H H methyl para-fluoro-phenylI-6 —(CH₂)₃OCH₃ H H ethyl phenyl I-7 —(CH₂)₂CO₂H methyl H H phenyl I-8—(CH₂)₂CO₂H H methyl H phenyl I-9 —(CH₂)₂CO₂H methyl methyl H phenylI-10 —(CH₂)₂CO₂H H H cyclopropryl phenyl I-11 —(CH₂)₂CO₂H H H Hpara-fluoro-phenyl I-12 —(CH₂)₂CO₂H H H H para-chloro-phenyl I-13—(CH₂)₂CO₂H H H H meta-fluoro-phenyl I-14 —(CH₂)₂CO₂H H H H3,5-difluorophenyl I-15 —(CH₂)₂CO₂H H H H 3,5-dimethylphenyl I-16—(CH₂)₂CO₂H H H H

I-17 —(CH₂)₂CO₂H H H H cyclohexyl I-18 —(CH₂)₂CO₂H H H H benzyl I-19—(CH₂)₂CO₂H H H H para-methoxybenzyl I-20 —(CH₂)₂CO₂H H H H—(CH₂)₂C(H)(CH₃)₂ I-21 —(CH₂)₃CO₂H H H H phenyl I-22 —(CH₂)₃CO₂H H H Hpara-chloro-phenyl I-23 —(CH₂)₃CO₂H H H H meta-fluoro-phenyl I-24—(CH₂)₃CO₂H H H H 3,5-difluorophenyl I-25 —(CH₂)₃CO₂H H H H3,5-dimethylphenyl I-26 —(CH₂)₃CO₂H H H H

I-27 —(CH₂)₃CO₂H H H H cyclohexyl I-28 —(CH₂)₃CO₂H H H H benzyl I-29—(CH₂)₃CO₂H H H H para-methoxybenzyl I-30 —(CH₂)₃CO₂H H H H—(CH₂)₂C(H)(CH₃)₂ I-31 —(CH₂)₂CO₂CH₃ H H H phenyl I-32 —(CH₂)₂CO₂CH₃ H Hethyl para-chloro-phenyl I-33 —(CH₂)₂CO₂CH₃ H H H meta-fluoro-phenylI-34 —(CH₂)₂CO₂CH₃ H H H 3,5-difluorophenyl I-35 —(CH₂)₂CO₂CH₃ H Hmethyl 3,5-dimethylphenyl I-36 —(CH₂)₂CO₂CH₃ H H H

I-37 —(CH₂)₂CO₂CH₃ H H H cyclohexyl I-38 —(CH₂)₂CO₂CH₃ H H methyl benzylI-39 —(CH₂)₂CO₂CH₃ H H H para-methoxybenzyl I-40 —(CH₂)₂CO₂CH₃ H Hmethyl —(CH₂)₂C(H)(CH₃)₂ I-41 —(CH₂)₂C(O)NH₂ H H H phenyl I-42—(CH₂)₂C(O)NH₂ H H ethyl para-chloro-phenyl I-43 —(CH₂)₂C(O)NH₂ H H Hmeta-fluoro-phenyl I-44 —(CH₂)₂C(O)NH₂ H H H 3,5-difluorophenyl I-45—(CH₂)₂C(O)NH₂ H H methyl 3,5-dimethylphenyl I-46 —(CH₂)₃OH H H H

I-47 —(CH₂)₃OH H H H cyclohexyl I-48 —(CH₂)₃OH H H methyl benzyl I-49—(CH₂)₃OH H H H para-methoxybenzyl I-50 —(CH₂)₃OH H H methyl—(CH₂)₂C(H)(CH₃)₂ I-51 —C(H)(CH₃)CO₂H H H H phenyl I-52 —C(H)(CH₃)CO₂H HH H para-chloro-phenyl I-53 —C(H)(CH₃)CO₂H H H H meta-fluoro-phenyl I-54—C(H)(CH₃)CO₂H H H H 3,5-difluorophenyl I-55 —C(H)(CH₃)CO₂H H H H3,5-dimethylphenyl I-56 —(CH₂)— C(H)(CH₃)CO₂H H H H

I-57 —(CH₂)— H H H cyclohexyl C(H)(CH₃)CO₂H I-58 —(CH₂)— H H H benzylC(H)(CH₃)CO₂H I-59 —(CH₂)— H H H para-methoxybenzyl C(H)(CH₃)CO₂H I-60—(CH₂)— H H H —(CH₂)₂C(H)(CH₃)₂ C(H)(CH₃)CO₂H I-61 —(CH₂)₂C(O)CH₃ H H Hphenyl I-62 —(CH₂)₂C(O)CH₃ H H ethyl para-chloro-phenyl I-63—(CH₂)₂C(O)CH₃ H H H meta-fluoro-phenyl I-64 —(CH₂)₂C(O)CH₃ H H H3,5-difluorophenyl I-65 —(CH₂)₂C(O)CH₃ H H methyl 3,5-dimethylphenylI-66 —(CH₂)₂C(O)CH₃ H H H

I-67 —(CH₂)₂C(O)CH₃ H H H cyclohexyl I-68 —(CH₂)₂C(O)CH₃ H H methylbenzyl I-69 —(CH₂)₂C(O)CH₃ H H H para-methoxybenzyl I-70 —(CH₂)₂C(O)CH₃H H methyl —(CH₂)₂C(H)(CH₃)₂ I-71 OH H H H H I-72 OH H H methyl H I-73CO₂H H H H H I-74 CO₂H H H methyl H I-75 —C(H)(CH₃)CO₂H H H H H

Methods for preparing compounds described herein are illustrated in thefollowing synthetic schemes. These schemes are given for the purpose ofillustrating the invention, and should not be regarded in any manner aslimiting the scope or the spirit of the invention. Starting materialsshown in the schemes can be obtained from commercial sources or can beprepared based on procedures described in the literature.

The synthetic route illustrated in Scheme II-1 depicts exemplaryprocedures for preparing esters, aldehydes, alcohols, and ketonecontaining compounds starting from commercially available carboxylicacid A. In the first step, commercially available carboxylic acid A issubjected to an esterification reaction with alcohol R′OH to produceester compound B. Esterification reactions are well known in theliterature and such reactions are often performed using an acidcatalyst, such as hydrochloric acid. Selective reduction of the estergroup in compound B using, for example, lithium borohydride, providesalcohol C. To the extent an aldehyde compound is desired, alcohol C canbe oxidized using procedures known in the literature for converting ahydroxyl group to an aldehyde, such as oxidation using Dess-MartinPeriodinane, to provide aldehyde D. Further, to the extent a ketonecompound is desired, aldehyde D can be reacted with an activated carbonnucleophile, such as R″MgCl, to form a secondary alcohol (not shown)that is then oxidized using procedures known in the literature, such asDess-Martin Periodinane, to form ketone compound E. Further descriptionof functional group conversation procedures are described in, forexample, “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming,eds., 1991-1992); Carey, F. A. and Sundberg, R. J. Advanced OrganicChemistry Part B: Reactions and Synthesis, 3^(rd) Ed.; Plenum Press: NewYork, 1990; and J. March, Advanced Organic Chemistry, McGraw Hill BookCompany, New York, (1992, 4^(th) edition). It is also appreciated thatif a particular compound contains a functional group sensitive to one ormore of the synthetic transformations described herein, thenconventional protecting group strategies are contemplated to be applied.For a description of protecting group strategies and procedures, see,for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in OrganicSynthesis, 2nd ed.; Wiley, New York, 1991.

Synthetic procedures in Scheme II-2 illustrate how chemical groups canbe added to the eastern portion of the fused heterotricyclic core. Forexample, palladium coupling procedures can be used to reactheteroaromatic bromide A1 with a boronic acid containing the desiredaromatic group, such as an optionally substituted phenyl group or anoptionally substituted 5-6 membered heteroaromatic group, to providecompound B1. A specific illustration of this synthetic procedure isprovided in Scheme II-3 where the first reaction sequence shows apara-methylphenyl group being attached to the fused heterotricyclic coreto provide compound B2 and the second reaction sequence shows amethylpyridinyl group being attached to the fused tricyclic core toprovide compound C_(2.) One advantage of the palladium coupling approachis that a large number of variously substituted aryl and heteroaromaticboronic acids are commercially available or may be easily prepared usingprocedures described in the literature.

Scheme II-4 illustrates procedures for preparing amides. Commerciallyavailable carboxylic acid A3 is subjected to esterification according tostandard literature procedures using methanol to provide ester compoundB3. Reaction of ester B3 with amine N(R′)H₂ (where R′ is alkyl) in thepresence of a base (e.g., potassium t-butoxide) according to proceduresdescribed in, for example, B. R. Kim et al. in Synthesis, 2012, 42-50,provides amide C3.

Synthetic procedures in Scheme II-5 illustrate how chemical groups canbe added to the western portion of the fused heterotricyclic core. Forexample, reaction of amide A4 with base (e.g., tert-butyl lithium)provides an organolithium intermediate (not shown) that will undergoreaction with epoxide B4 to provide alcohol C_(4.) Oxidation of alcoholC4 using standard procedures from the literature, such as Dess-MartinPeriodinane, provides ketone compound D4. Selective reduction of ketoneD4 using procedures from the literature (e.g., tosylhydrazine andcatechol borane) provides alkane E4. Removal of the protecting group(Pg) (e.g., by TBAF when Pg is tert-butyldimethylsilyl) provides alcoholF4, which can be oxidized to carboxylic acid G4 using oxidationprocedures described in the literature. For additional discussion ofoxidation, reduction, and protecting group removal procedures, see, forexample, “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming,eds., 1991-1992); Carey, F. A. and Sundberg, R. J. Advanced OrganicChemistry Part B: Reactions and Synthesis, 3^(rd) Ed.; Plenum Press: NewYork, 1990; J. March, Advanced Organic Chemistry, McGraw Hill BookCompany, New York, (1992, 4^(th) edition); and Greene, T. W.; Wuts, P.G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley, New York,1991.

B. Therapeutic Applications of Fused Heterotricyclic Organic Compounds

The invention provides methods for body contouring and/or reduction offat in a subject using the fused heterotricyclic organic compounds andpharmaceutical compositions described herein. Methods include the use offused heterotricyclic organic compounds described herein as stand-alonetherapeutic agents and/or as part of a combination therapy with anothermedicinal agent.

Cosmetic Methods of Modifying the Contour of a Subject's ExternallyExposed Body Part

One aspect of the invention provides a method of modifying the contourof a subject's externally exposed body part containing fat. The methodcomprises administering to said body part an amount of a fusedheterotricyclic organic compound described herein, such as a compound ofFormula I described above in Sub-Section A, effective to modify thecontour of said body part. Formula I, as described above in Sub-SectionA, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above in Sub-Section A.

In certain embodiments, the externally exposed body part containing fatis the subject's face, neck, chin, submental region, arm, thigh, knee,calf, buttocks, hips, or abdomen. In certain other embodiments, theexternally exposed body part containing fat is the subject's face. Incertain other embodiments, the externally exposed body part containingfat is the subject's chin or cheek. In certain embodiments, theexternally exposed body part is the subject's neck.

In certain embodiments, the subject experiences at least a 5% by weightreduction in the amount of fat in the subject's body part exposed tosaid compound. In certain other embodiments, the subject experiences atleast a 10% by weight reduction in the amount of fat in the subject'sbody part exposed to said compound. In certain embodiments, the subjectexperiences at least a 15% by weight reduction in the amount of fat inthe subject's body part exposed to said compound. In certain otherembodiments, the subject experiences at least a 25% by weight reductionin the amount of fat in the subject's body part exposed to saidcompound. In certain other embodiments, the subject experiences fromabout 1% to about 10%, about 10% to about 20%, about 20% to about 40%,about 40% to about 60%, about 60% to about 80%, about 1% to about 30%,or about 1% to about 50% by weight reduction in the amount of fat in thesubject's body part exposed to said compound.

In certain embodiments, the administering comprises injecting saidcompound into said body part.

In certain embodiments, the subject is an adult human. In certainembodiments, the subject is an animal, such as dog or cat.

In certain embodiments, the compound is one of the generic or specificcompounds described above in Sub-Section A, such as a compound ofFormula I, a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I, a compound ofFormula I-A, or a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Subcutaneous Fat

Another aspect of the invention provides a method of reducing the amountof subcutaneous fat in a subject. The method comprises exposingsubcutaneous fat in a subject to an effective amount of a fusedheterotricyclic organic compound described herein, such as a compound ofFormula I described above in Sub-Section A, to reduce the amount ofsubcutaneous fat in said subject. Formula I, as described above inSub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above in Sub-Section A.

In certain embodiments, the subcutaneous fat is located in the subject'sface, neck, chin, submental region, arm, thigh, knee, calf, buttocks,hips, or abdomen. In certain other embodiments, the subcutaneous fat islocated in subject's face. In certain other embodiments, thesubcutaneous fat is located in subject's neck.

In certain embodiments, the subject experiences at least a 5% by weightreduction in the amount of subcutaneous fat in the subject's body partexposed to said compound. In certain other embodiments, the subjectexperiences at least a 10% by weight reduction in the amount ofsubcutaneous fat in the subject's body part exposed to said compound. Incertain embodiments, the subject experiences at least a 15% by weightreduction in the amount of subcutaneous fat in the subject's body partexposed to said compound. In certain other embodiments, the subjectexperiences at least a 25% by weight reduction in the amount ofsubcutaneous fat in the subject's body part exposed to said compound. Incertain other embodiments, the subject experiences 1% to about 10%,about 10% to about 20%, about 20% to about 40%, about 40% to about 60%,about 60% to about 80%, about 1% to about 30%, or about 1% to about 50%by weight reduction in the amount of subcutaneous fat in the subject'sbody part exposed to said compound.

In certain embodiments, said exposing comprises injecting said compoundof Formula I into a region of subcutaneous fat.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described above in Sub-Section A, such as a compound ofFormula I, a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I, a compound ofFormula I-A, or a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I-A.

Methods of Inducing Retraction of Dermal Tissue

Another aspect of the invention provides a method for inducingretraction of dermal tissue in a subject. The method comprisesadministering an effective amount of a fused heterotricyclic organiccompound described herein, such as a compound of Formula I describedabove in Sub-Section A, to dermal tissue of a subject to induceretraction of dermal tissue. Formula I, as described above inSub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above in Sub-Section A.

In certain embodiments, said administering comprises injecting saidcompound into dermal tissue.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described above in Sub-Section A, such as a compound ofFormula I, a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I, a compound ofFormula I-A, or a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I-A.

Methods of Inducing Retraction of Subcutaneous Tissue

Another aspect of the invention provides a method for inducingretraction of subcutaneous tissue in a subject. The method comprisesadministering an effective amount of a fused heterotricyclic organiccompound described herein, such as a compound of Formula I describedabove in Sub-Section A, to subcutaneous tissue of a subject to induceretraction of subcutaneous tissue. Formula I, as described above inSub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above in Sub-Section A.

In certain embodiments, said administering comprises injecting saidcompound into subcutaneous tissue.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described above in Sub-Section A, such as a compound ofFormula I, a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I, a compound ofFormula I-A, or a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I-A.

Methods of Preventing Accumulation of Fat

Another aspect of the invention provides a method of preventing theaccumulation of fat in a subject. The method comprises administering toa subject in need thereof an effective amount of a fused heterotricyclicorganic compound described herein, such as a compound of Formula Idescribed above in Sub-Section A, to prevent accumulation of fat in thesubject. Formula I, as described above in Sub-Section A, is representedby:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above in Sub-Section A.

In certain embodiments, the fat is subcutaneous fat.

In certain embodiments, the accumulation of fat in a subject occurs inthe subject's face, neck, chin, submental region, arm, thigh, knee,calf, buttocks, hips, or abdomen.

In certain embodiments, said administering comprises injecting saidcompound into tissue in the region in which accumulation of fat is to beprevented.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described above in Sub-Section A, such as a compound ofFormula I, a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I, a compound ofFormula I-A, or a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I-A.

Methods of Treating Medical Disorders

Another aspect of the invention provides a method of treating a disorderselected from the group consisting of an adipose tissue tumor, fatembolism, dyslipidemia, or fatty liver disease in a subject. The methodcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a fused heterotricyclic organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to treat the disorder. Formula I, as described above in Sub-SectionA, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above in Sub-Section A.

In certain embodiments, the disorder is an adipose tissue tumor (e.g., alipoma). For example, in certain embodiments, the lipoma is anadenolipoma, angiolipoleiomyoma, angiolipoma, chondroid lipoma, corpuscallosum lipoma, hibernoma, intradermal spindle cell lipoma, neuralfibrolipoma, pleomorphic lipoma, spindle-cell lipoma, or a superficialsubcutaneous lipoma.

In certain embodiments, the disorder is fat embolism. In certain otherembodiments, the disorder is dyslipidemia. In certain other embodiments,the disorder is fatty liver disease. In certain embodiments, thedisorder is fatty liver disease due to alcohol-induced liver cirrhosis.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described above in Sub-Section A, such as a compound ofFormula I, a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I, a compound ofFormula I-A, or a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Fat or Cholesterol

Another aspect of the invention provides a method of reducing the amountof fat or cholesterol in a subject. The method comprises administeringto a subject in need thereof an effective amount of a fusedheterotricyclic organic compound described herein, such as a compound ofFormula I described above in Sub-Section A, to reduce the amount of fator cholesterol in the subject. Formula I, as described above inSub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined above in Sub-Section A.

In certain embodiments, the method reduces the amount of fat in asubject.

In certain embodiments, the method improves regulation of energy balancein the subject, lipid homeostatis, insulin sensitivity, blood pressurehomeostatis, or vascular health of the subject.

In certain embodiments, the method reduces the amount of cholesterol ina subject.

In certain embodiments, the subject suffers from a cardiovasculardisease. For example, in certain embodiments, the cardiovascular diseaseis coronary artery disease or peripheral vascular disease.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described above in Sub-Section A, such as a compound ofFormula I, a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I, a compound ofFormula I-A, or a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Mesenchymal Pre-Adipocyte Stem CellPrecursors

Another aspect of the invention provides a method of reducing the amountof mesenchymal pre-adipocyte stem cell precursors in a subject. Themethod comprises administering to a subject in need thereof an effectiveamount of a fused heterotricyclic organic compound described herein,such as a compound of Formula I described above in Sub-Section A, toreduce the amount of mesenchymal pre-adipocyte stem cell precursors inthe subject. Formula I, as above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Section II.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described above in Sub-Section A, such as a compound ofFormula I, a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I, a compound ofFormula I-A, or a compound embraced by one of the further embodimentsdescribing definitions for certain variables of Formula I-A.

Methods of Inducing Death of Adipocyte Cells

Another aspect of the invention provides a method of inducing the deathof an adipocyte cell. The method comprises exposing an adipocyte cell toan effective amount of a fused heterotricyclic organic compounddescribed herein, such as a compound of Formula I described above inSub-Section A, to induce death of the adipocyte cell. Formula I, asdescribed above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing Skin Aging

Another aspect of the invention provides a method of reducing skin agingin a subject. The method comprises administering to a subject in needthereof an effective amount of a fused heterotricyclic organic compounddescribed herein, such as a compound of Formula I described above inSub-Section A, to reduce the effects of skin aging. Formula I, asdescribed above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

The description above describes multiple embodiments relating to variousmethods, such as methods of body contouring and/or reducing fat in asubject using certain fused heterotricyclic organic compounds. Thepatent application specifically contemplates all combinations of theembodiments. For example, the invention contemplates body contouringand/or reducing fat in a subject by administering a therapeuticallyeffective amount of a compound of Formula I-A.

Combination Therapy

As indicated above, the invention embraces combination therapy, whichincludes the administration of a fused heterotricyclic organic compounddescribed herein (such as compound of Formula I or I-A described abovein Sub-Section A) and a second agent as part of a specific treatmentregimen intended to provide the beneficial effect from the co-action ofthese therapeutic agents. The beneficial effect of the combination mayinclude pharmacokinetic or pharmacodynamic co-action resulting from thecombination of therapeutic agents.

C. Pharmaceutical Compositions Containing Fused Heterotricyclic OrganicCompounds

The invention provides pharmaceutical compositions comprising a fusedheterotricyclic organic compound described herein, such as a compound ofFormula I or I-A described above in Sub-Section A, and apharmaceutically acceptable carrier. In certain embodiments, thepharmaceutical compositions preferably comprise an effective amount ofone or more of the fused heterotricyclic organic compounds describedabove (i.e., an amount effective to achieve one or more of thetherapeutic applications described above in Sub-Section B), formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail below in Section VI,pharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) parenteral administration by, forexample, subcutaneous, intramuscular, intravenous or epidural injectionas, for example, a sterile solution or suspension, or sustained-releaseformulation; (2) topical application, for example, as a cream, ointment,or a controlled-release patch or spray applied to the skin; (3) oraladministration, for example, drenches (aqueous or non-aqueous solutionsor suspensions), tablets (e.g., those targeted for buccal, sublingual,and/or systemic absorption), boluses, powders, granules, pastes forapplication to the tongue; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; (5) sublingually; (6) ocularly;(7) transdermally; or (8) nasally.

D. Medical Kits Containing Fused Heterotricyclic Organic Compounds

Another aspect of the invention provides a kit for body contouringand/or reducing the amount of fat in a subject. The kit comprises: i)instructions for body contouring and/or reducing the amount of fat in asubject (for example, modifying the contour of a subject's externallyexposed body part containing fat; reducing the amount of subcutaneousfat in a subject; inducing retraction of dermal tissue or subcutaneoustissue in a subject; preventing the accumulation of fat in a subject;treating a disorder selected from the group consisting of an adiposetissue tumor (e.g., a lipoma), fat embolism, dyslipidemia, or fattyliver disease in a subject; reducing the amount of fat or cholesterol ina subject; and reducing the amount of mesenchymal pre-adipocyte stemcell precursors in a subject); and ii) a fused heterotricyclic organiccompound described herein, such as a compound of Formula I describedabove in Sub-Section A. The kit may comprise one or more unit dosageforms containing an amount of a fused heterotricyclic organic compounddescribed herein, such as a compound of Formula I described above inSub-Section A, that is effective for body contouring and/or reduction offat in a subject.

III. Dipyrido-Pyrimidinone Organic Compounds & Their Use

Certain aspects of the invention provide dipyrido-pyrimidinone organiccompounds, pharmaceutical compositions containing such compounds,medical kits, and therapeutic applications using such compounds. Thesecompounds, pharmaceutical compositions, medical kits, and therapeuticapplications are described in more detail in the sections below.

A. Dipyrido-Pyrimidinone Organic Compounds

One aspect of the invention provides dipyrido-pyrimidinone organiccompounds. The dipyrido-pyrimidinone compounds are contemplated to beuseful in the methods, compositions, and kits described herein. Incertain embodiments, the dipyrido-pyrimidinone organic compound is acompound embraced by Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R⁶ each represent independently for each occurrence hydrogen,halogen, —(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl;

R² is —N(R⁷)R⁸, —OR⁷, —(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl;

R³ is hydrogen, —(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl;

R⁴ is aralkyl or heteroaralkyl, each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, hydroxyl,—(C₁-C₆)alkoxy, —N(R⁷)R⁸, —C(O)N(R⁷)R⁸, and —N(R⁷)C(O)R⁸;

R⁵ is hydrogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, —CO₂R⁷, —C(O)N(R⁷)R⁸,or —N(R⁷)C(O)R⁸;

R⁷ and R⁸ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl; or when R⁷ and R⁸ are attached tothe same nitrogen atom, then R⁷ and R⁸ may be taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocycle; and

n is 1, 2, or 3.

In certain embodiments, R¹ and R⁶ are hydrogen.

In certain embodiments, R² is —N(R⁷)R⁸ or —OR⁷. In certain otherembodiments, R² is —N(R⁷)R⁸. In certain other embodiments, R² is —NH₂.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R⁴ is aralkyl or heteroaralkyl, each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of chloro, fluoro —(C₁-C₆)alkyl,cyclopropyl, hydroxyl, and —(C₁-C₆)alkoxy. In certain other embodiments,R⁴ is aralkyl or heteroaralkyl, each of which is optionally substitutedwith methyl or methoxy. In certain other embodiments, R⁴ is benzyloptionally substituted with methyl or methoxy. In certain otherembodiments, R⁴ is benzyl. In certain other embodiments, R⁴ is—(C₁-C₃)alkylene-pyridinyl optionally substituted with methyl. Incertain other embodiments, R⁴ is —CH₂-pyridinyl.

In certain embodiments, R⁵ is hydrogen or —(C₁-C₆)alkyl. In certainother embodiments, R⁵ is hydrogen, methyl, or ethyl.

The description above describes multiple embodiments relating tocompounds of Formula I. The patent application specifically contemplatesall combinations of the embodiments.

In certain embodiments, the compound is a compound of Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein:

R² is —N(R⁷)R⁸;

R⁴ is aralkyl or heteroaralkyl, each of which is optionally substitutedwith 1, 2, or 3 substituents independently selected from the groupconsisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₅)cycloalkyl, hydroxyl,—(C₁-C₆)alkoxy, and —N(R⁷)R⁸;

R⁵ is hydrogen, —(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl;

R⁷ and R⁸ each represent independently hydrogen, —(C₁-C₆)alkyl, or—(C₃-C₆)cycloalkyl; or when R⁷ and R⁸ are attached to the same nitrogenatom, then R⁷ and R⁸ may be taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocycle.

In certain embodiments, R² is —NH₂.

In certain embodiments, R⁴ is aralkyl or heteroaralkyl, each of which isoptionally substituted with 1, 2, or 3 substituents independentlyselected from the group consisting of chloro, fluoro —(C₁-C₆)alkyl,cyclopropyl, hydroxyl, and —(C₁-C₆)alkoxy. In certain other embodiments,R⁴ is aralkyl or heteroaralkyl, each of which is optionally substitutedwith methyl or methoxy. In certain other embodiments, R⁴ is benzyloptionally substituted with methyl or methoxy. In certain otherembodiments, R⁴ is benzyl. In certain other embodiments, R⁴ is—(C₁-C₃)alkylene-pyridinyl optionally substituted with methyl. Incertain other embodiments, R⁴ is —CH₂-pyridinyl.

In certain embodiments, R⁵ is hydrogen. In certain other embodiments, R⁵is —(C₁-C₆)alkyl. In certain other embodiments, R⁵ is methyl or ethyl.

The description above describes multiple embodiments relating tocompounds of Formula I-A. The patent application specificallycontemplates all combinations of the embodiments.

In certain embodiments, the compound is one of the following or apharmaceutically acceptable salt thereof:

In certain other embodiments, the compound is one of the compoundslisted in Table 2 below or a pharmaceutically acceptable salt thereof.

TABLE 2

Compound No. R¹ R² R³ R⁴ R⁵ I-1 H NH₂ H benzyl H I-2 H NH₂ Hpara-methoxybenzyl H I-3 H NH₂ H ortho-methoxybenzyl H I-4 H NH₂ Hmeta-methoxybenzyl H I-5 H NH₂ H para-methylbenzyl H I-6 H NH₂ Hortho-methylbenzyl H I-7 H NH₂ H para-chlorobenzyl H I-8 H NH₂ Hortho-chlorobenzyl H I-9 H NH₂ H 3,5-difluorobenzyl H I-10 H NH₂ Hpara-cyclopropylbenzyl H I-11 H NH₂ H para-hydroxybenzyl H I-12 H NH₂ H

H I-13 H NH₂ H

H I-14 H NH₂ H

H I-15 H NH₂ H

H I-16 H NH₂ H

H I-17 H NH₂ H

H I-18 H NH₂ H

H I-19 H NH₂ H

H I-20 H NH₂ H

H I-21 H NH₂ H benzyl methyl I-22 H NH₂ H para-methoxybenzyl methyl I-23H NH₂ H ortho-methoxybenzyl methyl I-24 H NH₂ H meta-methoxybenzyl ethylI-25 H NH₂ H para-methylbenzyl methyl I-26 H NH₂ H ortho-methylbenzylmethyl I-27 H NH₂ H para-chlorobenzyl ethyl I-28 H NH₂ Hortho-chlorobenzyl methyl I-29 H NH₂ H 3,5-difluorobenzyl methyl I-30 HNH₂ H para-cyclopropylbenzyl ethyl I-31 H NH₂ H para-hydroxybenzylmethyl I-32 H NH₂ H

methyl I-33 H NH₂ H

methyl I-34 H NH₂ H

methyl I-35 H NH₂ H

methyl I-36 H NH₂ H

methyl I-37 H NH₂ H

ethyl I-38 H NH₂ H

ethyl I-39 H NH₂ H

methyl I-40 H NH₂ H

ethyl I-41 H —N(H)CH₃ H benzyl H I-42 methyl —N(H)CH₃ Hpara-methoxybenzyl H I-43 H —N(H)CH₃ methyl ortho-methoxybenzyl H I-44 H—OCH₃ H meta-methoxybenzyl H I-45 methyl —OCH₃ H para-methylbenzyl HI-46 H —OCH₃ methyl ortho-methylbenzyl H I-47 H —OH H para-chlorobenzylH I-48 methyl —OH H ortho-chlorobenzyl H I-49 H —OH methyl3,5-difluorobenzyl H I-50 H methyl H para-cyclopropylbenzyl H I-51methyl methyl H para-hydroxybenzyl H I-52 H —N(H)CH₃ H

H I-53 H —N(H)CH₃ H

H I-54 H —N(H)CH₃ methyl

H I-55 H —OCH₃ H

H I-56 H —OCH₃ H

H I-57 H —OCH₃ methyl

H I-58 H —OH H

H I-59 H —OH H

H I-60 H —OH methyl

H

Methods for preparing compounds described herein are illustrated in thefollowing synthetic schemes. These schemes are given for the purpose ofillustrating the invention, and should not be regarded in any manner aslimiting the scope or the spirit of the invention. Starting materialsshown in the schemes can be obtained from commercial sources or can beprepared based on procedures described in the literature.

The synthetic route illustrated in Scheme III-1 depicts exemplaryprocedures for preparing monoalkyl amides, dialkyl amides, andalkylimine compounds starting from amide A, which is commerciallyavailable at least when group A is phenyl, pyridinyl, andp-methoxylphenyl. In the first step, amide A is reacted with aprotecting group (Pg-X) that reacts with the imine functional group toprovide protected imine B. Exemplary reaction procedures includereacting amide A with

in the presence of a mild base, such as pyridine, to provide protectedimine B. Reaction of protected imine B with one molar equivalent ofmethyl iodide the presence of a mild base, such as pyridine, providesmonoalkyl amide C. The protecting group (Pg) in monoalkyl amide C can beremoved, such by treatment with TMSI when the protecting group is—CO₂-tert-butyl, to provide monoalkyl amide product E. Alternatively,monoalkyl amide C can be reacted with a second molar equivalent ofmethyl iodide in the presence of a mild base, such as pyridine, toprovide dialkyl amide D. The protecting group (Pg) in dialkyl amide Dcan be removed, such by treatment with TMSI when the protecting group is—CO₂-tert-butyl, to provide dialkyl amide product F. If desired,alkylimine G can be prepared by reacting dialkyl amide product F withone molar equivalent of methyl iodide in the presence of a mild base,such as pyridine. If further functional group manipulations are desired,such chemical transformations can be performed using proceduresdescribed in the literature, such as in, for example, “ComprehensiveOrganic Synthesis” (B. M. Trost & I. Fleming, eds., 1991-1992); Carey,F. A. and Sundberg, R. J. Advanced Organic Chemistry Part B: Reactionsand Synthesis, 3^(rd) Ed.; Plenum Press: New York, 1990; and J. March,Advanced Organic Chemistry, McGraw Hill Book Company, New York, (1992,4^(th) edition). For example, amides (such as the exocyclic primaryamide in Compound A) can be converted to a —CO₂H group by treatment withacid and water, and such a carboxylic acid can be converted to an alkylester, such as a —CO₂CH₃ group upon reaction of the —CO₂H group withmethanol in the presence of acid.

The synthetic route illustrated in Scheme III-2 depicts exemplaryprocedures for preparing compounds having various aralkyl orheteroaralkyl groups attached to the tricyclic core starting from amineA1. The procedure involves reacting amine A1 with an aralkyl halide or aheteroaralkyl halide B1 in the presence of a mild base to form syntheticintermediate C1. Protecting groups are removed from compound C1 toprovide final product D1. Exemplary protecting groups useful in suchtransformations are described in, for example, Greene, T. W.; Wuts, P.G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley, New York,1991. There are many aralkyl halides and heteroaralkyl halides B1available from commercial sources or that can be prepared according toprocedures described in the literature. In certain embodiments, compoundB1 is one of the following: para-cyclopropylbenzyl bromide,3,5-difluorobenzyl bromide.

B. Therapeutic Applications of Dipyrido-Pyrimidinone Organic Compounds

The invention provides methods for body contouring and/or reduction offat in a subject using the dipyrido-pyrimidinone organic compounds andpharmaceutical compositions described herein. Methods include the use ofdipyrido-pyrimidinone organic compounds described herein as stand-alonetherapeutic agents and/or as part of a combination therapy with anothermedicinal agent.

Cosmetic Methods of Modifying the Contour of a Subject's ExternallyExposed Body Part

One aspect of the invention provides a method of modifying the contourof a subject's externally exposed body part containing fat. The methodcomprises administering to said body part an amount of adipyrido-pyrimidinone organic compound described herein, such as acompound of Formula I described above in Sub-Section A, effective tomodify the contour of said body part. Formula I, as described above inSub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the externally exposed body part containing fatis the subject's face, neck, chin, submental region, arm, thigh, knee,calf, buttocks, hips, or abdomen. In certain other embodiments, theexternally exposed body part containing fat is the subject's face. Incertain other embodiments, the externally exposed body part containingfat is the subject's chin or cheek. In certain embodiments, theexternally exposed body part is the subject's neck.

In certain embodiments, the subject experiences at least a 5% by weightreduction in the amount of fat in the subject's body part exposed tosaid compound. In certain other embodiments, the subject experiences atleast a 10% by weight reduction in the amount of fat in the subject'sbody part exposed to said compound. In certain embodiments, the subjectexperiences at least a 15% by weight reduction in the amount of fat inthe subject's body part exposed to said compound. In certain otherembodiments, the subject experiences at least a 25% by weight reductionin the amount of fat in the subject's body part exposed to saidcompound. In certain other embodiments, the subject experiences fromabout 1% to about 10%, about 10% to about 20%, about 20% to about 40%,about 40% to about 60%, about 60% to about 80%, about 1% to about 30%,or about 1% to about 50% by weight reduction in the amount of fat in thesubject's body part exposed to said compound.

In certain embodiments, the administering comprises injecting saidcompound into said body part.

In certain embodiments, the subject is an adult human. In certainembodiments, the subject is an animal, such as dog or cat.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Subcutaneous Fat

Another aspect of the invention provides a method of reducing the amountof subcutaneous fat in a subject. The method comprises exposingsubcutaneous fat in a subject to an effective amount of adipyrido-pyrimidinone organic compound described herein, such as acompound of Formula I described above in Sub-Section A, to reduce theamount of subcutaneous fat in said subject. Formula I, as describedabove in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the subcutaneous fat is located in the subject'sface, neck, chin, submental region, arm, thigh, knee, calf, buttocks,hips, or abdomen. In certain other embodiments, the subcutaneous fat islocated in subject's face. In certain other embodiments, thesubcutaneous fat is located in subject's neck.

In certain embodiments, the subject experiences at least a 5% by weightreduction in the amount of subcutaneous fat in the subject's body partexposed to said compound. In certain other embodiments, the subjectexperiences at least a 10% by weight reduction in the amount ofsubcutaneous fat in the subject's body part exposed to said compound. Incertain embodiments, the subject experiences at least a 15% by weightreduction in the amount of subcutaneous fat in the subject's body partexposed to said compound. In certain other embodiments, the subjectexperiences at least a 25% by weight reduction in the amount ofsubcutaneous fat in the subject's body part exposed to said compound. Incertain other embodiments, the subject experiences 1% to about 10%,about 10% to about 20%, about 20% to about 40%, about 40% to about 60%,about 60% to about 80%, about 1% to about 30%, or about 1% to about 50%by weight reduction in the amount of subcutaneous fat in the subject'sbody part exposed to said compound.

In certain embodiments, said exposing comprises injecting said compoundof Formula I into a region of subcutaneous fat.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Inducing Retraction of Dermal Tissue

Another aspect of the invention provides a method for inducingretraction of dermal tissue in a subject. The method comprisesadministering an effective amount of a dipyrido-pyrimidinone organiccompound described herein, such as a compound of Formula I describedabove in Sub-Section A, to dermal tissue of a subject to induceretraction of dermal tissue. Formula I, as described above inSub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, said administering comprises injecting saidcompound into dermal tissue.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Inducing Retraction of Subcutaneous Tissue

Another aspect of the invention provides a method for inducingretraction of subcutaneous tissue in a subject. The method comprisesadministering an effective amount of a dipyrido-pyrimidinone organiccompound described herein, such as a compound of Formula I describedabove in Sub-Section A, to subcutaneous tissue of a subject to induceretraction of subcutaneous tissue. Formula I, as described above inSub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, said administering comprises injecting saidcompound into subcutaneous tissue.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Preventing Accumulation of Fat

Another aspect of the invention provides a method of preventing theaccumulation of fat in a subject. The method comprises administering toa subject in need thereof an effective amount of a dipyrido-pyrimidinoneorganic compound described herein, such as a compound of Formula Idescribed above in Sub-Section A, to prevent accumulation of fat in thesubject. Formula I, as described above in Sub-Section A, is representedby:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the fat is subcutaneous fat.

In certain embodiments, the accumulation of fat in a subject occurs inthe subject's face, neck, chin, submental region, arm, thigh, knee,calf, buttocks, hips, or abdomen.

In certain embodiments, said administering comprises injecting saidcompound into tissue in the region in which accumulation of fat is to beprevented.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Treating Medical Disorders

Another aspect of the invention provides a method of treating a disorderselected from the group consisting of an adipose tissue tumor, fatembolism, dyslipidemia, or fatty liver disease in a subject. The methodcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a dipyrido-pyrimidinone organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to treat the disorder. Formula I, as described above in Sub-SectionA, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the disorder is an adipose tissue tumor (e.g., alipoma). For example, in certain embodiments, the lipoma is anadenolipoma, angiolipoleiomyoma, angiolipoma, chondroid lipoma, corpuscallosum lipoma, hibernoma, intradermal spindle cell lipoma, neuralfibrolipoma, pleomorphic lipoma, spindle-cell lipoma, or a superficialsubcutaneous lipoma.

In certain embodiments, the disorder is fat embolism. In certain otherembodiments, the disorder is dyslipidemia. In certain other embodiments,the disorder is fatty liver disease. In certain embodiments, thedisorder is fatty liver disease due to alcohol-induced liver cirrhosis.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Fat or Cholesterol

Another aspect of the invention provides a method of reducing the amountof fat or cholesterol in a subject. The method comprises administeringto a subject in need thereof an effective amount of adipyrido-pyrimidinone organic compound described herein, such as acompound of Formula I described above in Sub-Section A, to reduce theamount of fat or cholesterol in the subject. Formula I, as describedabove in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the method reduces the amount of fat in asubject.

In certain embodiments, the method improves regulation of energy balancein the subject, lipid homeostatis, insulin sensitivity, blood pressurehomeostatis, or vascular health of the subject.

In certain embodiments, the method reduces the amount of cholesterol ina subject.

In certain embodiments, the subject suffers from a cardiovasculardisease. For example, in certain embodiments, the cardiovascular diseaseis coronary artery disease or peripheral vascular disease.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Mesenchymal Pre-Adipocyte Stem CellPrecursors

Another aspect of the invention provides a method of reducing the amountof mesenchymal pre-adipocyte stem cell precursors in a subject. Themethod comprises administering to a subject in need thereof an effectiveamount of a dipyrido-pyrimidinone organic compound described herein,such as a compound of Formula I described above in Sub-Section A, toreduce the amount of mesenchymal pre-adipocyte stem cell precursors inthe subject. Formula I, as described above in Sub-Section A, isrepresented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Inducing Death of Adipocyte Cells

Another aspect of the invention provides a method of inducing the deathof an adipocyte cell. The method comprises exposing an adipocyte cell toan effective amount of a dipyrido-pyrimidinone organic compounddescribed herein, such as a compound of Formula I, to induce death ofthe adipocyte cell. Formula I, as described above in Sub-Section A, isrepresented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing Skin Aging

Another aspect of the invention provides a method of reducing skin agingin a subject. The method comprises administering to a subject in needthereof an effective amount of a dipyrido-pyrimidinone organic compounddescribed herein, such as a compound of Formula I described above inSub-Section A, to reduce the effects of skin aging. Formula I, asdescribed above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

The description above describes multiple embodiments relating to variousmethods, such as methods of body contouring and/or reducing fat in asubject using certain dipyrido-pyrimidinone organic compounds. Thepatent application specifically contemplates all combinations of theembodiments. For example, the invention contemplates body contouringand/or reducing fat in a subject by administering a therapeuticallyeffective amount of a compound of Formula I-A.

Combination Therapy

As indicated above, the invention embraces combination therapy, whichincludes the administration of a dipyrido-pyrimidinone organic compounddescribed herein (such as compound of Formula I or I-A described abovein Sub-Section A) and a second agent as part of a specific treatmentregimen intended to provide the beneficial effect from the co-action ofthese therapeutic agents. The beneficial effect of the combination mayinclude pharmacokinetic or pharmacodynamic co-action resulting from thecombination of therapeutic agents.

C. Pharmaceutical Compositions Containing Dipyrido-Pyrimidinone OrganicCompounds

The invention provides pharmaceutical compositions comprising adipyrido-pyrimidinone organic compound described herein, such as acompound of Formula I or I-A described above in Sub-Section A, and apharmaceutically acceptable carrier. In certain embodiments, thepharmaceutical compositions preferably comprise an effective amount ofone or more of the dipyrido-pyrimidinone organic compounds describedabove (i.e., an amount effective to achieve one or more of thetherapeutic applications described in Sub-Section B herein), formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail below in Section VI,pharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) parenteral administration by, forexample, subcutaneous, intramuscular, intravenous or epidural injectionas, for example, a sterile solution or suspension, or sustained-releaseformulation; (2) topical application, for example, as a cream, ointment,or a controlled-release patch or spray applied to the skin; (3) oraladministration, for example, drenches (aqueous or non-aqueous solutionsor suspensions), tablets (e.g., those targeted for buccal, sublingual,and/or systemic absorption), boluses, powders, granules, pastes forapplication to the tongue; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; (5) sublingually; (6) ocularly;(7) transdermally; or (8) nasally.

D. Medical Kits Containing Dipyrido-Pyrimidinone Organic Compounds

Another aspect of the invention provides a kit for body contouringand/or reducing the amount of fat in a subject. The kit comprises: i)instructions for body contouring and/or reducing the amount of fat in asubject (for example, modifying the contour of a subject's externallyexposed body part containing fat; reducing the amount of subcutaneousfat in a subject; inducing retraction of dermal tissue or subcutaneoustissue in a subject; preventing the accumulation of fat in a subject;treating a disorder selected from the group consisting of an adiposetissue tumor (e.g., a lipoma), fat embolism, dyslipidemia, or fattyliver disease in a subject; reducing the amount of fat or cholesterol ina subject; and reducing the amount of mesenchymal pre-adipocyte stemcell precursors in a subject); and ii) a dipyrido-pyrimidinone organiccompound described herein, such as a compound of Formula I describedabove in Sub-Section A. The kit may comprise one or more unit dosageforms containing an amount of a dipyrido-pyrimidinone organic compounddescribed herein, such as a compound of Formula described above inSub-Section A, that is effective for body contouring and/or reduction offat in a subject.

The description above describes multiple aspects and embodiments of theinvention, including dipyrido-pyrimidinone organic compounds,compositions comprising dipyrido-pyrimidinone organic compounds, methodsof using the dipyrido-pyrimidinone organic compounds, and kits. Thepatent application specifically contemplates all combinations andpermutations of the aspects and embodiments. For example, the inventioncontemplates body contouring and/or reducing fat in a human patient byadministering a therapeutically effective amount of a compound ofFormula I-A described above in Sub-Section A. Further, for example, theinvention contemplates a kit for body contouring and/or reduction of fatin a subject, the kit comprising instructions for body contouring and/orreducing fat in a subject and ii) a dipyrido-pyrimidinone organiccompound described herein, such as a compound of Formula I-A describedabove in Sub-Section A.

IV. Tetrahydropyrimido-Furo-Isoquinolinone Organic Compounds & Their Use

Certain aspects of the invention providetetrahydropyrimido-furo-isoquinolinone organic compounds, pharmaceuticalcompositions containing such compounds, medical kits, and therapeuticapplications using such compounds. These compounds, pharmaceuticalcompositions, medical kits, and therapeutic applications are describedin more detail in the sections below.

A. Tetrahydropyrimido-Furo-Isoquinolinone Organic Compounds

One aspect of the invention providestetrahydropyrimido-furo-isoquinolinone organic compounds. Thetetrahydropyrimido-furo-isoquinolinone organic compounds arecontemplated to be useful in the methods, compositions, and kitsdescribed herein. In certain embodiments, thetetrahydropyrimido-furo-isoquinolinone organic compound is a compoundembraced by Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R³ each represent independently for each occurrence hydrogen,halogen, —(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl;

R² is —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, phenyl, 5-6 memberedheteroaryl, aralkyl, or —(C₁-C₆)alkoxy, wherein said cycloalkyl, phenyl,5-6 membered heteroaryl, and aralkyl are optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, hydroxyl, and—(C₁-C₆)alkoxy;

R⁴ is —(C₁-C₆)alkylene-X¹ or —(C₃-C₆)cycloalkyl-X¹;

X¹ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, —CO₂R⁶, —C(O)R⁶, —OR⁶, or —N(R⁵)R⁶;

R⁵ and R⁶ each represent independently hydrogen, —(C₁-C₆)alkyl, or—(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached to the same nitrogenatom, then R⁵ and R⁶ may be taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocycle; and

n is 1, 2, or 3.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, R² is —(C₁-C₆)alkyl. In certain otherembodiments, R² is methyl, ethyl, n-propyl, or isopropyl. In certainother embodiments, R² is phenyl. In certain other embodiments, R² isphenyl substituted with 1, 2, or 3 substituents independently selectedfrom the group consisting of halogen, —(C₁-C₆)alkyl, hydroxyl, and—(C₁-C₆)alkoxy.

In certain embodiments, R³ is hydrogen.

In certain embodiments, R⁴ is —(C₁-C₆)alkylene-X¹. In certain otherembodiments, R⁴ is —(C₁-C₆)alkylene-C(O)N(R⁵)R⁶. In certain otherembodiments, R⁴ is —CH₂—C(O)N(R⁵)R⁶. In certain other embodiments, R⁴ is—(C₁-C₆)alkylene-C(O)NH₂. In certain other embodiments, R⁴ is—CH₂—C(O)NH₂.

In certain embodiments, X¹ is —C(O)N(R⁵)R⁶. In certain otherembodiments, X¹ is —N(R⁵)C(O)R⁶. In certain other embodiments, X¹ is—CO₂R⁶. In certain other embodiments, X¹ is —N(R⁵)R⁶.

In certain embodiments, R⁵ and R⁶ each represent independently hydrogenor —(C₁-C₆)alkyl. In certain other embodiments, R⁵ and R⁶ are hydrogen.

The description above describes multiple embodiments relating tocompounds of Formula I. The patent application specifically contemplatesall combinations of the embodiments.

In certain embodiments, the compound is a compound of Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein:

R² is —(C₁-C₆)alkyl or phenyl, wherein said phenyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,hydroxyl, and —(C₁-C₆)alkoxy;

R⁴ is —(C₁-C₆)alkylene-X¹ or —(C₃-C₆)cycloalkyl-X¹;

X¹ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, or —CO₂R⁶; and

R⁵ and R⁶ each represent independently hydrogen or —(C₁-C₆)alkyl, orwhen R⁵ and R⁶ are attached to the same nitrogen atom, then R⁵ and R⁶may be taken together with the nitrogen atom to which they are attachedto form a 3-7 membered heterocycle.

In certain embodiments, R² is —(C₁-C₆)alkyl. In certain otherembodiments, R² is methyl, ethyl, n-propyl, or isopropyl. In certainother embodiments, R² is phenyl. In certain other embodiments, R² isphenyl substituted with 1, 2, or 3 substituents independently selectedfrom the group consisting of halogen, —(C₁-C₆)alkyl, hydroxyl, and—(C₁-C₆)alkoxy.

In certain embodiments, R⁴ is —CH₂—C(O)N(R⁵)R⁶. In certain otherembodiments, R⁴ is —(C₁-C₆)alkylene-C(O)NH₂. In certain otherembodiments, R⁴ is —CH₂—C(O)NH₂.

The description above describes multiple embodiments relating tocompounds of Formula I-A. The patent application specificallycontemplates all combinations of the embodiments.

In certain embodiments, the compound is one of the following or apharmaceutically acceptable salt thereof:

In certain other embodiments, the compound is one of the compoundslisted in Table 3 below or a pharmaceutically acceptable salt thereof.

TABLE 3

Compound No. R^(1A) R^(1B) R² R³ R⁴ I-1 H H methyl H —CH₂CONH₂ I-2 H Hethyl H —CH₂CONH₂ I-3 H H phenyl H —CH₂CONH₂ I-4 H H para-chlorophenyl H—CH₂CONH₂ I-5 H H para-methylphenyl H —CH₂CONH₂ I-6 H Hmeta-methoxyphenyl H —CH₂CONH₂ I-7 H H benzyl H —CH₂CONH₂ I-8 H Hpara-chlorobenzyl H —CH₂CONH₂ I-9 H H

H —CH₂CONH₂ I-10 H H

H —CH₂CONH₂ I-11 H H

H —CH₂CONH₂ I-12 H H

H —CH₂CONH₂ I-13 H H

H —CH₂CONH₂ I-14 H H

H —CH₂CONH₂ I-15 H H

H —CH₂CONH₂ I-16 H H methyl H —(CH₂)₂CONH₂ I-17 H H ethyl H —(CH₂)₂CONH₂I-18 CH₃ H phenyl H —(CH₂)₂CONH₂ I-19 H CH₃ para-chlorophenyl H—(CH₂)₂CONH₂ I-20 H H para-methylphenyl CH₃ —(CH₂)₂CONH₂ I-21 CH₃ CH₃meta-methoxyphenyl CH₃ —(CH₂)₂CONH₂ I-22 F H benzyl H —(CH₂)₂CONH₂ I-23H F para-chlorobenzyl H —(CH₂)₂CONH₂ I-24 H H

H —(CH₂)₂CONH₂ I-25 H CH₃

H —(CH₂)₂CONH₂ I-26 H H

CH₃ —(CH₂)₂CONH₂ I-27 CH₃ H

CH₃ —(CH₂)₂CONH₂ I-28 H H

H —(CH₂)₂CONH₂ I-29 H CH₃

H —(CH₂)₂CONH₂ I-30 H H

CH₃ —(CH₂)₂CONH₂ I-31 H H methyl H —CH₂CO₂H I-32 H H ethyl H —CH₂CO₂HI-33 H H phenyl H —CH₂CO₂H I-34 H H para-chlorophenyl H —CH₂CO₂H I-35 HH cyclopropyl H —CH₂CO₂H I-36 H H cyclopentyl H —CH₂CO₂H I-37 H Hcyclohexyl H —CH₂CO₂H I-38 H H

H —CH₂CO₂H I-39 H H

H —CH₂CO₂H I-40 H H

H —CH₂CO₂H I-41 H H methyl H —CH₂CH₂—NH₂ I-42 H H ethyl H —CH₂CH₂—NH₂I-43 H H phenyl H —CH₂CH₂—NH₂ I-44 H H para-chlorophenyl H —CH₂CH₂—NH₂I-45 H H cyclopropyl H —CH₂CH₂—NH₂ I-46 H H cyclopentyl H —CH₂CH₂—NH₂I-47 H H cyclohexyl H —CH₂CH₂—NH₂ I-48 H H

H —CH₂CH₂—NH₂ I-49 H H

H —CH₂CH₂—NH₂ I-50 H H

H —CH₂CH₂—NH₂ I-51 H H methyl H —CH₂CO₂CH₃ I-52 H H ethyl H —CH₂CO₂CH₃I-53 H H phenyl H —CH₂CO₂CH₃ I-54 H H para-chlorophenyl H —CH₂CO₂CH₃I-55 H H cyclopropyl H —CH₂CO₂CH₃ I-56 H H cyclopentyl H —CH₂CO₂CH₃ I-57H H cyclohexyl H —CH₂CO₂CH₃ I-58 H H

H —CH₂CO₂CH₃ I-59 H H

H —CH₂CO₂CH₃ I-60 H H

H —CH₂CO₂CH₃

Methods for preparing compounds described herein are illustrated in thefollowing synthetic schemes. These schemes are given for the purpose ofillustrating the invention, and should not be regarded in any manner aslimiting the scope or the spirit of the invention. Starting materialsshown in the schemes can be obtained from commercial sources or can beprepared based on procedures described in the literature.

The synthetic route illustrated in Scheme IV-1 depicts exemplaryprocedures for preparing amines, carboxylic acids, alkyl esters, andaldehyde compounds starting from amide A, which is commerciallyavailable when, for example, R is methyl, ethyl, or phenyl. In the firststep, amide A is subjected to acid-catalyzed hydrolysis, such as usinghydrochloric acid and water, to provide carboxylic acid C. If desired,carboxylic acid C can be subjected to an esterification reaction with analcohol, such as methanol, to produce ester compound D. Esterificationreactions are well known in the literature and such reactions are oftenperformed using an acid catalyst, such as hydrochloric acid. Selectivereduction of the ester group in compound D provides aldehyde E, and suchreductions can be carried out using procedures described in theliterature, such as selective reduction using diisobutylaluminum hydrideat low temperature. Separately, if desired, amine compound B can beprepared from amide A by selective reduction of the exocyclic amidegroup. Also, if desired, the exocyclic amide group in compound A or theprimary amino group in compound B can be alkylated, such as by reactingwith one equivalent of methyl iodide in the presence of a hindered base,to provide a monoalkylated amide or amine, respectively.

A variety of substituents can be attached to the pyridinyl portion ofthe multicyclic core of tetrahydropyrimido-furo-isoquinolinones. Anexemplary procedure for installing such substituents is illustrated inScheme IV-2 below. Starting from commercially available amide A1, aprotecting group is installed on the exocyclic amide to form compoundB1. Various protecting groups are described in the literature, and onepossible protecting group is —C(O)CH₂CH₂Si(CH₃)₃, which is installed byreacting amide A1 with ClC(O)CH₂CH₂Si(CH₃)₃ in the presence of a mildbase, such as pyridine or imidazole. Then, selective oxidation of thebenzylic methyl group on compound B1 provides alcohol C1. Alcohol C1 isconverted to bromide D1 using, for example, PBR₃ or other agents orprocedures known in the art for converting a primary hydroxyl group to abromide. Bromide D1 is then reacted with bis(pinacolato)diboron in thepresence of a palladium catalyst and tBu₂MeP.HBF₄ to providealkylboronate E1. For exemplary description of procedures for formingalkylboronates, see, for example, Joshi-Pangu et al. in J. Org. Chem.,2012, vol. 77, 6629-6633. Next, alkylboronate E1 is subjected topalladium coupling conditions with an aryl bromide, heteroaryl bromide,or alkyl bromide to provide compound F1. The protecting group on F1 canbe removed, such as by using tetrabutylammonium fluoride when theprotecting group is —C(O)CH₂CH₂Si(CH₃)₃, to provide final product G1.Further description of functional group conversation procedures aredescribed in, for example, “Comprehensive Organic Synthesis” (B. M.Trost & I. Fleming, eds., 1991-1992); Carey, F. A. and Sundberg, R. J.Advanced Organic Chemistry Part B: Reactions and Synthesis, 3^(rd) Ed.;Plenum Press: New York, 1990; and J. March, Advanced Organic Chemistry,McGraw Hill Book Company, New York, (1992, 4^(th) edition). It is alsoappreciated that if a particular compound contains a functional groupsensitive to one or more of the synthetic transformations describedherein, then conventional protecting group strategies are contemplatedto be applied. For a description of protecting group strategies andprocedures, see, for example, Greene, T. W.; Wuts, P. G. M. ProtectiveGroups in Organic Synthesis, 2nd ed.; Wiley, New York, 1991.

B. Therapeutic Applications of Tetrahydropyrimido-Furo-IsoquinolinoneOrganic Compounds

The invention provides methods for body contouring and/or reduction offat in a subject using the tetrahydropyrimido-furo-isoquinolinoneorganic compounds and pharmaceutical compositions described herein.Methods include the use of tetrahydropyrimido-furo-isoquinolinoneorganic compounds described herein as stand-alone therapeutic agentsand/or as part of a combination therapy with another medicinal agent.

Cosmetic Methods of Modifying the Contour of a Subject's ExternallyExposed Body Part

One aspect of the invention provides a method of modifying the contourof a subject's externally exposed body part containing fat. The methodcomprises administering to said body part an amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, effective to modify the contour of said body part. Formula I, asdescribed above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the externally exposed body part containing fatis the subject's face, neck, chin, submental region, arm, thigh, knee,calf, buttocks, hips, or abdomen. In certain other embodiments, theexternally exposed body part containing fat is the subject's face. Incertain other embodiments, the externally exposed body part containingfat is the subject's chin or cheek. In certain embodiments, theexternally exposed body part is the subject's neck.

In certain embodiments, the subject experiences at least a 5% by weightreduction in the amount of fat in the subject's body part exposed tosaid compound. In certain other embodiments, the subject experiences atleast a 10% by weight reduction in the amount of fat in the subject'sbody part exposed to said compound. In certain embodiments, the subjectexperiences at least a 15% by weight reduction in the amount of fat inthe subject's body part exposed to said compound. In certain otherembodiments, the subject experiences at least a 25% by weight reductionin the amount of fat in the subject's body part exposed to saidcompound. In certain other embodiments, the subject experiences fromabout 1% to about 10%, about 10% to about 20%, about 20% to about 40%,about 40% to about 60%, about 60% to about 80%, about 1% to about 30%,or about 1% to about 50% by weight reduction in the amount of fat in thesubject's body part exposed to said compound.

In certain embodiments, the administering comprises injecting saidcompound into said body part.

In certain embodiments, the subject is an adult human. In certainembodiments, the subject is an animal, such as dog or cat.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Subcutaneous Fat

Another aspect of the invention provides a method of reducing the amountof subcutaneous fat in a subject. The method comprises exposingsubcutaneous fat in a subject to an effective amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to reduce the amount of subcutaneous fat in said subject. Formula I,as described above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the subcutaneous fat is located in the subject'sface, neck, chin, submental region, arm, thigh, knee, calf, buttocks,hips, or abdomen. In certain other embodiments, the subcutaneous fat islocated in subject's face. In certain other embodiments, thesubcutaneous fat is located in subject's neck.

In certain embodiments, the subject experiences at least a 5% by weightreduction in the amount of subcutaneous fat in the subject's body partexposed to said compound. In certain other embodiments, the subjectexperiences at least a 10% by weight reduction in the amount ofsubcutaneous fat in the subject's body part exposed to said compound. Incertain embodiments, the subject experiences at least a 15% by weightreduction in the amount of subcutaneous fat in the subject's body partexposed to said compound. In certain other embodiments, the subjectexperiences at least a 25% by weight reduction in the amount ofsubcutaneous fat in the subject's body part exposed to said compound. Incertain other embodiments, the subject experiences 1% to about 10%,about 10% to about 20%, about 20% to about 40%, about 40% to about 60%,about 60% to about 80%, about 1% to about 30%, or about 1% to about 50%by weight reduction in the amount of subcutaneous fat in the subject'sbody part exposed to said compound.

In certain embodiments, said exposing comprises injecting said compoundof Formula I into a region of subcutaneous fat.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Inducing Retraction of Dermal Tissue

Another aspect of the invention provides a method for inducingretraction of dermal tissue in a subject. The method comprisesadministering an effective amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to dermal tissue of a subject to induce retraction of dermal tissue.Formula I, as described above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, said administering comprises injecting saidcompound into dermal tissue.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Inducing Retraction of Subcutaneous Tissue

Another aspect of the invention provides a method for inducingretraction of subcutaneous tissue in a subject. The method comprisesadministering an effective amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to subcutaneous tissue of a subject to induce retraction ofsubcutaneous tissue. Formula I, as described above in Sub-Section A, isrepresented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, said administering comprises injecting saidcompound into subcutaneous tissue.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Preventing Accumulation of Fat

Another aspect of the invention provides a method of preventing theaccumulation of fat in a subject. The method comprises administering toa subject in need thereof an effective amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to prevent accumulation of fat in the subject. Formula I, asdescribed above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the fat is subcutaneous fat.

In certain embodiments, the accumulation of fat in a subject occurs inthe subject's face, neck, chin, submental region, arm, thigh, knee,calf, buttocks, hips, or abdomen.

In certain embodiments, said administering comprises injecting saidcompound into tissue in the region in which accumulation of fat is to beprevented.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Treating Medical Disorders

Another aspect of the invention provides a method of treating a disorderselected from the group consisting of an adipose tissue tumor, fatembolism, dyslipidemia, or fatty liver disease in a subject. The methodcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a tetrahydropyrimido-furo-isoquinolinone organiccompound described herein, such as a compound of Formula I describedabove in Sub-Section A, to treat the disorder. Formula I, as describedabove in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the disorder is an adipose tissue tumor (e.g., alipoma). For example, in certain embodiments, the lipoma is anadenolipoma, angiolipoleiomyoma, angiolipoma, chondroid lipoma, corpuscallosum lipoma, hibernoma, intradermal spindle cell lipoma, neuralfibrolipoma, pleomorphic lipoma, spindle-cell lipoma, or a superficialsubcutaneous lipoma.

In certain embodiments, the disorder is fat embolism. In certain otherembodiments, the disorder is dyslipidemia. In certain other embodiments,the disorder is fatty liver disease. In certain embodiments, thedisorder is fatty liver disease due to alcohol-induced liver cirrhosis.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Fat or Cholesterol

Another aspect of the invention provides a method of reducing the amountof fat or cholesterol in a subject. The method comprises administeringto a subject in need thereof an effective amount of atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to reduce the amount of fat or cholesterol in the subject. Formula I,as described above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the method reduces the amount of fat in asubject.

In certain embodiments, the method improves regulation of energy balancein the subject, lipid homeostatis, insulin sensitivity, blood pressurehomeostatis, or vascular health of the subject.

In certain embodiments, the method reduces the amount of cholesterol ina subject.

In certain embodiments, the subject suffers from a cardiovasculardisease. For example, in certain embodiments, the cardiovascular diseaseis coronary artery disease or peripheral vascular disease.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Mesenchymal Pre-Adipocyte Stem CellPrecursors

Another aspect of the invention provides a method of reducing the amountof mesenchymal pre-adipocyte stem cell precursors in a subject. Themethod comprises administering to a subject in need thereof an effectiveamount of a tetrahydropyrimido-furo-isoquinolinone organic compounddescribed herein, such as a compound of Formula I described above inSub-Section A, to reduce the amount of mesenchymal pre-adipocyte stemcell precursors in the subject. Formula I, as described above inSub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Inducing Death of Adipocyte Cells

Another aspect of the invention provides a method of inducing the deathof an adipocyte cell. The method comprises exposing an adipocyte cell toan effective amount of a tetrahydropyrimido-furo-isoquinolinone organiccompound described herein, such as a compound of Formula I describedabove in Sub-Section A, to induce death of the adipocyte cell. FormulaI, as described above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing Skin Aging

Another aspect of the invention provides a method of reducing skin agingin a subject. The method comprises administering to a subject in needthereof an effective amount of a tetrahydropyrimido-furo-isoquinolinoneorganic compound described herein, such as a compound of Formula Idescribed above in Sub-Section A, to reduce the effects of skin aging.Formula I, as described above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

The description above describes multiple embodiments relating to variousmethods, such as methods of body contouring and/or reducing fat in asubject using certain tetrahydropyrimido-furo-isoquinolinone organiccompounds. The patent application specifically contemplates allcombinations of the embodiments. For example, the invention contemplatesbody contouring and/or reducing fat in a subject by administering atherapeutically effective amount of a compound of Formula I-A.

Combination Therapy

As indicated above, the invention embraces combination therapy, whichincludes the administration of a tetrahydropyrimido-furo-isoquinolinoneorganic compound described herein (such as compound of Formula I or I-Adescribed above in Sub-Section A) and a second agent as part of aspecific treatment regimen intended to provide the beneficial effectfrom the co-action of these therapeutic agents. The beneficial effect ofthe combination may include pharmacokinetic or pharmacodynamic co-actionresulting from the combination of therapeutic agents.

C. Pharmaceutical Compositions ContainingTetrahydropyrimido-Furo-Isoquinolinone Organic Compounds

The invention provides pharmaceutical compositions comprising atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I or I-A described above inSub-Section A, and a pharmaceutically acceptable carrier. In certainembodiments, the pharmaceutical compositions preferably comprise aneffective amount of one or more of thetetrahydropyrimido-furo-isoquinolinone organic compounds described above(i.e., an amount effective to achieve one or more of the therapeuticapplications described above in Sub-Section B), formulated together withone or more pharmaceutically acceptable carriers (additives) and/ordiluents. As described in detail below in Section VI, pharmaceuticalcompositions of the present invention may be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: (1) parenteral administration by, for example, subcutaneous,intramuscular, intravenous or epidural injection as, for example, asterile solution or suspension, or sustained-release formulation; (2)topical application, for example, as a cream, ointment, or acontrolled-release patch or spray applied to the skin; (3) oraladministration, for example, drenches (aqueous or non-aqueous solutionsor suspensions), tablets (e.g., those targeted for buccal, sublingual,and/or systemic absorption), boluses, powders, granules, pastes forapplication to the tongue; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; (5) sublingually; (6) ocularly;(7) transdermally; or (8) nasally.

D. Medical Kits Containing Tetrahydropyrimido-Furo-IsoquinolinoneOrganic Compounds

Another aspect of the invention provides a kit for body contouringand/or reducing the amount of fat in a subject. The kit comprises: i)instructions for body contouring and/or reducing the amount of fat in asubject (for example, modifying the contour of a subject's externallyexposed body part containing fat; reducing the amount of subcutaneousfat in a subject; inducing retraction of dermal tissue or subcutaneoustissue in a subject; preventing the accumulation of fat in a subject;treating a disorder selected from the group consisting of an adiposetissue tumor (e.g., a lipoma), fat embolism, dyslipidemia, or fattyliver disease in a subject; reducing the amount of fat or cholesterol ina subject; and reducing the amount of mesenchymal pre-adipocyte stemcell precursors in a subject); and ii) atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA. The kit may comprise one or more unit dosage forms containing anamount of a tetrahydropyrimido-furo-isoquinolinone organic compounddescribed herein, such as a compound of Formula I described above inSub-Section A, that is effective for body contouring and/or reduction offat in a subject.

The description above describes multiple aspects and embodiments of theinvention, including tetrahydropyrimido-furo-isoquinolinone organiccompounds, compositions comprisingtetrahydropyrimido-furo-isoquinolinone organic compounds, methods ofusing the tetrahydropyrimido-furo-isoquinolinone organic compounds, andkits. The patent application specifically contemplates all combinationsand permutations of the aspects and embodiments. For example, theinvention contemplates body contouring and/or reducing fat in a humanpatient by administering a therapeutically effective amount of acompound of Formula I-A described above in Sub-Section A. Further, forexample, the invention contemplates a kit for body contouring and/orreduction of fat in a subject, the kit comprising instructions for bodycontouring and/or reducing fat in a subject and ii) atetrahydropyrimido-furo-isoquinolinone organic compound describedherein, such as a compound of Formula I-A described above in Sub-SectionA.

V. Tetrahydrobenzo[4,5]Imidazo[1,2-a]Pyrazine Organic Compounds & TheirUse

Certain aspects of the invention providetetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compounds,pharmaceutical compositions containing such compounds, medical kits, andtherapeutic applications using such compounds. These compounds,pharmaceutical compositions, medical kits, and therapeutic applicationsare described in more detail in the sections below.

A. Tetrahydrobenzo[4,5]Imidazo[1,2-a]Pyrazine Organic Compounds

One aspect of the invention providestetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compounds. Thetetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compounds arecontemplated to be useful in the methods, compositions, and kitsdescribed herein. In certain embodiments, thetetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound is acompound embraced by Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is phenyl, 5-6 membered heteroaryl, aralkyl, —(C₁-C₆)alkyl,—(C₃-C₆)cycloalkyl —(C₁-C₆)alkylene-OH, or—(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein said phenyl, 5-6 memberedheteroaryl, aralkyl, and cycloalkyl are optionally substituted with 1,2, or 3 substituents independently selected from the group consisting ofhalogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, hydroxyl, —(C₁-C₆)alkoxy,and —N(R⁵)R⁶;

R² and R³ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or halogen;

R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, —CO₂R⁶, —C(O)R⁶,—(C₁-C₆)alkylene-N(R⁵)R⁶, —(C₁-C₆)alkylene-OR⁶, or —(C₁-C₆)alkoxy; and

R⁵ and R⁶ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached tothe same nitrogen atom, then R⁵ and R⁶ may be taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocycle; and

n and m each represent independently 1 or 2.

In certain embodiments, R¹ is phenyl substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, hydroxyl, —(C₁-C₆)alkoxy,and —N(R⁵)R⁶. In certain other embodiments, R¹ is phenyl substitutedwith a methoxy group and optionally 1 or 2 additional substituentsindependently selected from the group consisting of halogen and—(C₁-C₆)alkyl. In certain other embodiments, R¹ is methoxyphenyl. Incertain other embodiments, R¹—(C₁-C₆)alkylene-OH.

In certain embodiments, R² and R³ are hydrogen.

In certain embodiments, R⁴ is —C(O)N(R⁵)R⁶. In certain otherembodiments, R⁴ is —C(O)NH₂.

The description above describes multiple embodiments relating tocompounds of Formula I. The patent application specifically contemplatesall combinations of the embodiments.

In certain embodiments, the compound is a compound of Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is phenyl, —(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl,wherein said phenyl is optionally substituted with 1, 2, or 3substituents independently selected from the group consisting ofhalogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, hydroxyl, and—(C₁-C₆)alkoxy;

R² and R³ each represent independently for each occurrence hydrogen andmethyl;

R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, or —(C₁-C₂)alkylene-N(R⁵)R⁶; and

R⁵ and R⁶ each represent independently hydrogen, —(C₁-C₆)alkyl, or—(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached to the same nitrogenatom, then R⁵ and R⁶ may be taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocycle.

In certain embodiments, R¹ is phenyl substituted with 1, 2, or 3substituents independently selected from the group consisting of—(C₁-C₃)alkyl, —(C₃-C₆)cycloalkyl, hydroxyl, and —(C₁-C₆)alkoxy. Incertain other embodiments, R¹ is phenyl substituted with a methoxy groupand optionally 1 or 2 —(C₁-C₆)alkyl groups. In certain otherembodiments, R¹ is methoxyphenyl. In certain other embodiments,R¹—(C₁-C₆)alkylene-OH.

In certain embodiments, R⁴ is —C(O)N(R⁵)R⁶. In certain otherembodiments, R⁴ is —C(O)NH₂.

The description above describes multiple embodiments relating tocompounds of Formula I-A. The patent application specificallycontemplates all combinations of the embodiments.

In certain embodiments, the compound is one of the following or apharmaceutically acceptable salt thereof:

In certain other embodiments, the compound is one of the compoundslisted in Table 4 below or a pharmaceutically acceptable salt thereof.

TABLE 4

Compound No. R¹ R² R³ R⁴ I-1 2-methoxy-phenyl H H —CONH₂ I-2 3-methoxy-phenyl H H —CONH₂ I-3 4-methoxy-phenyl H H —CONH₂ I-4

H H —CONH₂ I-5

H H —CONH₂ I-6

H H —CONH₂ I-7 benzyl H H —CONH₂ I-8 4-methoxy-benzyl H H —CONH₂ I-9—(CH₂)₃—OH H H —CONH₂ I-10 —(CH₂)₂—OH H H —CONH₂ I-11 —CH₂CH(CH₃)—OH H H—CONH₂ I-12

H H —CONH₂ I-13

H H —CONH₂ I-14

H H —CONH₂ I-15

H H —CONH₂ I-16

H H —CONH₂ I-17

H H —CONH₂ I-18 —(CH₂)₃—OCH₃ H H —CONH₂ I-19 —(CH₂)₂—OCH₃ H H —CONH₂I-20

H H —CONH₂ I-21 2-methoxy-phenyl CH₃ H —CONH₂ I-22 3-methoxy-phenyl HCH₃ —CONH₂ I-23 4-methoxy-phenyl CH₃ CH₃ —CONH₂ I-24

H CH₃ —CONH₂ I-25

H CH₃ —CONH₂ I-26

CH₃ CH₃ —CONH₂ I-27 benzyl CH₃ H —CONH₂ I-28 4-methoxy-benzyl H CH₃—CONH₂ I-29 —(CH₂)₃—OH CH₃ CH₃ —CONH₂ I-30 —(CH₂)₂—OH CH₃ H —CONH₂ I-31—CH₂CH(CH₃)—OH H CH₃ —CONH₂ I-32

CH₃ CH₃ —CONH₂ I-33

CH₃ H —CONH₂ I-34

H CH₃ —CONH₂ I-35

CH₃ F —CONH₂ I-36

F H —CONH₂ I-37

H F —CONH₂ I-38 —(CH₂)₃—OCH₃ CH₃ Cl —CONH₂ I-39 —(CH₂)₂—OCH₃ Cl H —CONH₂I-40

H Cl —CONH₂ I-41 2-methoxy-phenyl H H —CON(H)CH₃ I-42 3-methoxy-phenyl HH —CON(H)CH₃ I-43 4-methoxy-phenyl H H —CON(H)CH₃ I-44

H H —CON(H)CH₃ I-45

H H —CON(H)CH₃ I-46

H H —CON(H)CH₂CH₃ I-47 benzyl H H —CON(H)CH₂CH₃ I-48 4-methoxy-benzyl HH —CON(H)CH₂CH₃ I-49 —(CH₂)₃-OH H H —CON(H)CH₂CH₃ I-50 —(CH₂)₂—OH H H—CON(H)CH₂CH₃ I-51 2-methoxy-phenyl H H —CO₂H I-52 3-methoxy-phenyl H H—CO₂H I-53 4-methoxy-phenyl H H —CO₂H I-54

H H —CO₂H I-55

H H —CO₂H I-56

H H —CO₂H I-57 benzyl H H —CO₂H I-58 4-methoxy-benzyl H H —CO₂H I-59—(CH₂)₃—OH H H —CO₂H I-60 —(CH₂)₂—OH H H —CO₂H I-61 2-methoxy-phenyl H H—CO₂CH₃ I-62 3-methoxy-phenyl H H —CO₂CH₃ I-63 4-methoxy-phenyl H H—CO₂CH₃ I-64

H H —CO₂CH₃ I-65

H H —CO₂CH₃ I-66

H H —CO₂CH₃ I-67 benzyl H H —CO₂CH₃ I-68 4-methoxy-benzyl H H —CO₂CH₃I-69 —(CH₂)₃—OH H H —CO₂CH₃ I-70 —(CH₂)₂—OH H H —CO₂CH₃ I-712-methoxy-phenyl H H —CHNH₂ I-72 3-methoxy-phenyl H H —CHNH₂ I-734-methoxy-phenyl H H —CHNH₂ I-74

H H —CHNH₂ I-75

H H —CHNH₂ I-76

H H —CHNH₂ I-77 benzyl H H —CHNH₂ I-78 4-methoxy-benzyl H H —CHNH₂ I-79—(CH₂)₃—OH H H —CHNH₂ I-80 —(CH₂)₂—OH H H —CHNH₂

Methods for preparing compounds described herein are illustrated in thefollowing synthetic schemes. These schemes are given for the purpose ofillustrating the invention, and should not be regarded in any manner aslimiting the scope or the spirit of the invention. Starting materialsshown in the schemes can be obtained from commercial sources or can beprepared based on procedures described in the literature.

The synthetic route illustrated in Scheme V-1 depicts exemplaryprocedures for preparing carboxylic acids, alkyl esters, and ketonecompounds starting from aryl amide A, which is commercially availablewhen, for example, R is ortho-methoxyphenyl, para-methoxyphenyl, and3-hydroxypropyl. In the first step, amide A is subjected toacid-catalyzed hydrolysis, such as using hydrochloric acid and water, toprovide carboxylic acid B. If desired, carboxylic acid B can besubjected to an esterification reaction with an alcohol, such asmethanol, to produce ester compound C. Esterification reactions are wellknown in the literature and such reactions are often performed using anacid catalyst, such as hydrochloric acid. Reduction of the ester groupin compound C can be performed using literature procedures to providealdehyde D. Reaction of aldehyde D with a Grignard reagent, such asCH₃MgCl, provides alcohol E that can be oxidized using procedures knownin the literature for converting a hydroxyl group to a ketone, such asoxidation using Dess-Martin Periodinane, to provide ketone F. Furtherdescription of functional group conversation procedures are describedin, for example, “Comprehensive Organic Synthesis” (B. M. Trost & I.Fleming, eds., 1991-1992); Carey, F. A. and Sundberg, R. J. AdvancedOrganic Chemistry Part B: Reactions and Synthesis, 3^(rd) Ed.; PlenumPress: New York, 1990; and J. March, Advanced Organic Chemistry, McGrawHill Book Company, New York, (1992, 4^(th) edition). It is appreciatedthat if a particular compound contains a functional group sensitive toone or more of the synthetic transformations described herein, thenconventional protecting group strategies are contemplated to be applied.For a description of protecting group strategies and procedures, see,for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in OrganicSynthesis, 2nd ed.; Wiley, New York, 1991.

The synthetic route illustrated in Scheme V-2 depicts exemplaryprocedures for preparing amine compounds starting aryl amide A, which iscommercially available when, for example, R is ortho-methoxyphenyl,para-methoxyphenyl, and 3-hydroxypropyl. In this procedure, amide A1 isreduced using, for example, lithium aluminum hydride, to provide amineB1.

The synthetic route illustrated in Scheme V-3 depicts exemplaryprocedures for attaching various groups to the piperazine nitrogen atomof the tricyclic core of compound A2. The synthetic route involvesreacting amine A2 with an aryl bromide or heteroaryl bromide B2 in thepresence of a palladium catalyst to provide compound C2. Furtherdescription of such palladium coupling reactions are available in theliterature. Protecting groups (Pg) can be removed from compound C2 usingstandard procedures, such as those described in, for example, Greene, T.W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.;Wiley, New York, 1991. Such amide protecting groups are commonly knownin the literature, such as described in Greene, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis, 2nd ed.; Wiley, New York, 1991.Alternatively, other groups (e.g., alkyl groups, substituted alkylgroups, aralkyl groups, heteroalkyl groups) can be added to thepiperazine nitrogen atom of the tricyclic core of compound A2 byreacting compound A2 with an alkyl bromide, substituted alkyl bromide,aralkyl bromide, or heteroaralkyl bromide in an N-alkylation reaction.

B. Therapeutic Applications ofTetrahydrobenzo[4,5]Imidazo[1,2-a]Pyrazine Organic Compounds

The invention provides methods for body contouring and/or reduction offat in a subject using the tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazineorganic compounds and pharmaceutical compositions described herein.Methods include the use of tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazineorganic compounds described herein as stand-alone therapeutic agentsand/or as part of a combination therapy with another medicinal agent.

Cosmetic Methods of Modifying the Contour of a Subject's ExternallyExposed Body Part

One aspect of the invention provides a method of modifying the contourof a subject's externally exposed body part containing fat. The methodcomprises administering to said body part an amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, effective to modify the contour of said body part. Formula I, asdescribed above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the externally exposed body part containing fatis the subject's face, neck, chin, submental region, arm, thigh, knee,calf, buttocks, hips, or abdomen. In certain other embodiments, theexternally exposed body part containing fat is the subject's face. Incertain other embodiments, the externally exposed body part containingfat is the subject's chin or cheek. In certain embodiments, theexternally exposed body part is the subject's neck.

In certain embodiments, the subject experiences at least a 5% by weightreduction in the amount of fat in the subject's body part exposed tosaid compound. In certain other embodiments, the subject experiences atleast a 10% by weight reduction in the amount of fat in the subject'sbody part exposed to said compound. In certain embodiments, the subjectexperiences at least a 15% by weight reduction in the amount of fat inthe subject's body part exposed to said compound. In certain otherembodiments, the subject experiences at least a 25% by weight reductionin the amount of fat in the subject's body part exposed to saidcompound. In certain other embodiments, the subject experiences fromabout 1% to about 10%, about 10% to about 20%, about 20% to about 40%,about 40% to about 60%, about 60% to about 80%, about 1% to about 30%,or about 1% to about 50% by weight reduction in the amount of fat in thesubject's body part exposed to said compound.

In certain embodiments, the administering comprises injecting saidcompound into said body part.

In certain embodiments, the subject is an adult human. In certainembodiments, the subject is an animal, such as dog or cat.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Subcutaneous Fat

Another aspect of the invention provides a method of reducing the amountof subcutaneous fat in a subject. The method comprises exposingsubcutaneous fat in a subject to an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to reduce the amount of subcutaneous fat in said subject. Formula I,as described above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the subcutaneous fat is located in the subject'sface, neck, chin, submental region, arm, thigh, knee, calf, buttocks,hips, or abdomen. In certain other embodiments, the subcutaneous fat islocated in subject's face. In certain other embodiments, thesubcutaneous fat is located in subject's neck.

In certain embodiments, the subject experiences at least a 5% by weightreduction in the amount of subcutaneous fat in the subject's body partexposed to said compound. In certain other embodiments, the subjectexperiences at least a 10% by weight reduction in the amount ofsubcutaneous fat in the subject's body part exposed to said compound. Incertain embodiments, the subject experiences at least a 15% by weightreduction in the amount of subcutaneous fat in the subject's body partexposed to said compound. In certain other embodiments, the subjectexperiences at least a 25% by weight reduction in the amount ofsubcutaneous fat in the subject's body part exposed to said compound. Incertain other embodiments, the subject experiences 1% to about 10%,about 10% to about 20%, about 20% to about 40%, about 40% to about 60%,about 60% to about 80%, about 1% to about 30%, or about 1% to about 50%by weight reduction in the amount of subcutaneous fat in the subject'sbody part exposed to said compound.

In certain embodiments, said exposing comprises injecting said compoundof Formula I into a region of subcutaneous fat.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Inducing Retraction of Dermal Tissue

Another aspect of the invention provides a method for inducingretraction of dermal tissue in a subject. The method comprisesadministering an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to dermal tissue of a subject to induce retraction of dermal tissue.Formula I, as described above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, said administering comprises injecting saidcompound into dermal tissue.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Inducing Retraction of Subcutaneous Tissue

Another aspect of the invention provides a method for inducingretraction of subcutaneous tissue in a subject. The method comprisesadministering an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to subcutaneous tissue of a subject to induce retraction ofsubcutaneous tissue. Formula I, as described above in Sub-Section A, isrepresented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, said administering comprises injecting saidcompound into subcutaneous tissue.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Preventing Accumulation of Fat

Another aspect of the invention provides a method of preventing theaccumulation of fat in a subject. The method comprises administering toa subject in need thereof an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to prevent accumulation of fat in the subject. Formula I, asdescribed above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the fat is subcutaneous fat.

In certain embodiments, the accumulation of fat in a subject occurs inthe subject's face, neck, chin, submental region, arm, thigh, knee,calf, buttocks, hips, or abdomen.

In certain embodiments, said administering comprises injecting saidcompound into tissue in the region in which accumulation of fat is to beprevented.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Treating Medical Disorders

Another aspect of the invention provides a method of treating a disorderselected from the group consisting of an adipose tissue tumor, fatembolism, dyslipidemia, or fatty liver disease in a subject. The methodcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organiccompound described herein, such as a compound of Formula I describedabove in Sub-Section A, to treat the disorder. Formula I, as describedabove in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the disorder is an adipose tissue tumor (e.g., alipoma). For example, in certain embodiments, the lipoma is anadenolipoma, angiolipoleiomyoma, angiolipoma, chondroid lipoma, corpuscallosum lipoma, hibernoma, intradermal spindle cell lipoma, neuralfibrolipoma, pleomorphic lipoma, spindle-cell lipoma, or a superficialsubcutaneous lipoma.

In certain embodiments, the disorder is fat embolism. In certain otherembodiments, the disorder is dyslipidemia. In certain other embodiments,the disorder is fatty liver disease. In certain embodiments, thedisorder is fatty liver disease due to alcohol-induced liver cirrhosis.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Fat or Cholesterol

Another aspect of the invention provides a method of reducing the amountof fat or cholesterol in a subject. The method comprises administeringto a subject in need thereof an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to reduce the amount of fat or cholesterol in the subject. Formula I,as described above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the method reduces the amount of fat in asubject.

In certain embodiments, the method improves regulation of energy balancein the subject, lipid homeostatis, insulin sensitivity, blood pressurehomeostatis, or vascular health of the subject.

In certain embodiments, the method reduces the amount of cholesterol ina subject.

In certain embodiments, the subject suffers from a cardiovasculardisease. For example, in certain embodiments, the cardiovascular diseaseis coronary artery disease or peripheral vascular disease.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing the Amount of Mesenchymal Pre-Adipocyte Stem CellPrecursors

Another aspect of the invention provides a method of reducing the amountof mesenchymal pre-adipocyte stem cell precursors in a subject. Themethod comprises administering to a subject in need thereof an effectiveamount of a tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compounddescribed herein, such as a compound of Formula I described above inSub-Section A, to reduce the amount of mesenchymal pre-adipocyte stemcell precursors in the subject. Formula I, as described above inSub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the subject is an adult human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Inducing Death of Adipocyte Cells

Another aspect of the invention provides a method of inducing the deathof an adipocyte cell. The method comprises exposing an adipocyte cell toan effective amount of a tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazineorganic compound described herein, such as a compound of Formula Idescribed above in Sub-Section A, to induce death of the adipocyte cell.Formula I, as described above in Sub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

Methods of Reducing Skin Aging

Another aspect of the invention provides a method of reducing skin agingin a subject. The method comprises administering to a subject in needthereof an effective amount of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA, to reduce the effects of skin aging. Formula I, as described above inSub-Section A, is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in Sub-Section A.

In certain embodiments, the compound is one of the generic or specificcompounds described in Sub-Section A, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A.

The description above describes multiple embodiments relating to variousmethods, such as methods of body contouring and/or reducing fat in asubject using certain tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organiccompounds. The patent application specifically contemplates allcombinations of the embodiments. For example, the invention contemplatesbody contouring and/or reducing fat in a subject by administering atherapeutically effective amount of a compound of Formula I-A.

Combination Therapy

As indicated above, the invention embraces combination therapy, whichincludes the administration of atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein (such as compound of Formula I or I-A described above inSub-Section A) and a second agent as part of a specific treatmentregimen intended to provide the beneficial effect from the co-action ofthese therapeutic agents. The beneficial effect of the combination mayinclude pharmacokinetic or pharmacodynamic co-action resulting from thecombination of therapeutic agents.

C. Pharmaceutical Compositions ContainingTetrahydrobenzo[4,5]Imidazo[1,2-a]Pyrazine Organic Compounds

The invention provides pharmaceutical compositions comprising atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I or I-A described above inSub-Section A, and a pharmaceutically acceptable carrier. In certainembodiments, the pharmaceutical compositions preferably comprise aneffective amount of one or more of thetetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compounds describedabove (i.e., an amount effective to achieve one or more of thetherapeutic applications described above in Sub-Section B), formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail below in Section VI,pharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) parenteral administration by, forexample, subcutaneous, intramuscular, intravenous or epidural injectionas, for example, a sterile solution or suspension, or sustained-releaseformulation; (2) topical application, for example, as a cream, ointment,or a controlled-release patch or spray applied to the skin; (3) oraladministration, for example, drenches (aqueous or non-aqueous solutionsor suspensions), tablets (e.g., those targeted for buccal, sublingual,and/or systemic absorption), boluses, powders, granules, pastes forapplication to the tongue; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; (5) sublingually; (6) ocularly;(7) transdermally; or (8) nasally.

D. Medical Kits Containing Tetrahydrobenzo[4,5]Imidazo[1,2-a]PyrazineOrganic Compounds

Another aspect of the invention provides a kit for body contouringand/or reducing the amount of fat in a subject. The kit comprises: i)instructions for body contouring and/or reducing the amount of fat in asubject (for example, modifying the contour of a subject's externallyexposed body part containing fat; reducing the amount of subcutaneousfat in a subject; inducing retraction of dermal tissue or subcutaneoustissue in a subject; preventing the accumulation of fat in a subject;treating a disorder selected from the group consisting of an adiposetissue tumor (e.g., a lipoma), fat embolism, dyslipidemia, or fattyliver disease in a subject; reducing the amount of fat or cholesterol ina subject; and reducing the amount of mesenchymal pre-adipocyte stemcell precursors in a subject); and ii) atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I described above in Sub-SectionA. The kit may comprise one or more unit dosage forms containing anamount of a tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compounddescribed herein, such as a compound of Formula I described above inSub-Section A, that is effective for body contouring and/or reduction offat in a subject.

The description above describes multiple aspects and embodiments of theinvention, including tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organiccompounds, compositions comprisingtetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compounds, methods ofusing the tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compounds,and kits. The patent application specifically contemplates allcombinations and permutations of the aspects and embodiments. Forexample, the invention contemplates body contouring and/or reducing fatin a human patient by administering a therapeutically effective amountof a compound of Formula I-A described above in Sub-Section A. Further,for example, the invention contemplates a kit for body contouring and/orreduction of fat in a subject, the kit comprising instructions for bodycontouring and/or reducing fat in a subject and ii) atetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compound describedherein, such as a compound of Formula I-A described above in Sub-SectionA.

VI. Pharmaceutical Compositions

The invention provides pharmaceutical compositions comprising a fusedheterocyclic organic compound described herein and a pharmaceuticallyacceptable carrier. In certain embodiments, the pharmaceuticalcompositions preferably comprise an effective amount of one or more ofthe fused heterocyclic organic compounds described above, formulatedtogether with one or more pharmaceutically acceptable carriers(additives) and/or diluents. As described in detail below, thepharmaceutical compositions of the present invention may be speciallyformulated for administration in solid or liquid form, including thoseadapted for the following: (1) parenteral administration by, forexample, subcutaneous, intramuscular, intravenous or epidural injectionas, for example, a sterile solution or suspension, or sustained-releaseformulation; (2) topical application, for example, as a cream, ointment,or a controlled-release patch or spray applied to the skin; (3) oraladministration, for example, drenches (aqueous or non-aqueous solutionsor suspensions), tablets (e.g., those targeted for buccal, sublingual,and/or systemic absorption), boluses, powders, granules, pastes forapplication to the tongue; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; (5) sublingually; (6) ocularly;(7) transdermally; or (8) nasally.

Particularly preferred pharmaceutical compositions are those formulatedfor injection, particularly subcutaneous injection. Such pharmaceuticalcompositions desirably comprise water and one or more excipients.Exemplary excipients include, for example, salts (e.g., sodium acetate,sodium chloride, sodium citrate, sodium phosphate, sodium sulfate,succinate, tris, phosphate buffered saline (i.e., PBS), and the like),amino acids (e.g., arginine, histidine, glycine, and the like),detergents (e.g., polysorbate 20, polysorbate 0, Triton X-100, and thelike), carbohydrates (e.g., sucrose, trehalose, and the like), polyols(e.g., glycerol, sorbitol, and the like), cyclodextrins (e.g.,2-hydroxypropyl-beta-cyclodextrin, sulfobutyl ether beta-cyclodextrin,and the like), celluloses, liposomes, micelle forming agents (e.g., bileacids), polymeric carriers (e.g., polyesters, polyanhydrides,polyalkylene ethers such as polyethylene glycol and polyethylene glycol400, and the like), propylene glycol, ethanol, dimethylsulfoxide (DMSO),and dimethylacetamide (DMA).

In certain embodiments, the pharmaceutical composition is formulated forreducing the amount of fat in a subject. In certain other embodiments,the pharmaceutical composition is formulated for reducing the amount ofsubcutaneous fat in a subject.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration.

The amount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will generally be that amountof the compound which produces a therapeutic effect. Generally, out ofone hundred percent, this amount will range from about 0.1 percent toabout ninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

The preparations of the present invention may be given parenterally,topically, orally, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form; by injection, infusion orinhalation; topically by lotion or ointment; and rectally bysuppositories.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Preferably, the compounds areadministered at about 0.01 mg/kg to about 200 mg/kg, more preferably atabout 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5mg/kg to about 50 mg/kg. When the compounds described herein areco-administered with another agent (e.g., as sensitizing agents), theeffective amount may be less than when the agent is used alone.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

The description above describes multiple aspects and embodiments of theinvention, including fused heterotricyclic organic compounds,compositions comprising fused heterocyclic organic compounds, methods ofusing the fused heterocyclic organic compounds, and kits. The patentapplication specifically contemplates all combinations and permutationsof the aspects and embodiments. For example, the invention contemplatesbody contouring and/or reducing fat in a human patient by administeringa therapeutically effective amount of a compound of Formula I-A inSection II, Sub-Section A. Further, for example, the inventioncontemplates a kit for body contouring and/or reduction of fat in asubject, the kit comprising instructions for body contouring and/orreducing fat in a subject and ii) a fused heterotricyclic organiccompound described herein, such as a compound of Formula I-A in SectionII, Sub-Section A.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1 Evaluation of Adipocyte Cell Cytotoxicity for Exemplary FusedHeterotricyclic Organic Compounds

Exemplary fused heterotricyclic organic compounds of the invention wereevaluated for adipocyte cell cytotoxicity using a cellviability/cytotoxicity assay commercially available from MolecularProbes, located in Eugene Oreg.

Materials and Methods

Adipocytes were maintained using standard cell culture procedures.Approximately, 1-2 million cells/mL were incubated with 10 mg/mL of testcompound or control at 37° C. for varying amounts of time up to 24hours. Following incubation with a test compound or control, aliquots ofcells in solution were transferred to a 96-well microplate and preparedaccording to the manufacturer's instructions. Cells were exposed tocalcein AM and ethidium homodimer-1, each purchased from MolecularProbes. Following incubation of the cells in presence of calcein AM andethidium homodimer-1, the fluorescence signal of calcein and ethidiumwas then measured using a SpectraMax Multi-Mode Microplate Reader usingoptical filters and excitation and emission wavelengths of 494 nm/517 nmand 528 nm/617 nm for calcein and ethidium bromide, respectively. Testcompounds listed in Table 5 below were purchased from a commercialvendor.

Results and Discussion

The time dependent effects of test compounds on both cell viability andcell toxicity were evaluated using a fluorescence assay that measuresplasma membrane integrity and intracellular enzyme activity. Briefly,live cells are determined by the increased fluorescence signal ofcalcein AM upon enzymatic conversion. In contrast, the ethidiumfluorescence signal is dramatically increased upon entering a cell withdamaged membranes and binding to nucleic acids. The ratio of ethidium tocalcein fluorescence can also be used to measure the relative amount oflive and dead cells. The ethidium signal was used as a measure of celldeath following the protocols outlined by the assay manufacturer.

The cell membrane disruption effects of various test compounds werecompared to the known cytotoxic compound deoxycholic acid (DC), and thecombination of phosphatidylcholine and deoxycholic acid (PC/DC) (i.e.,as positive controls). Saline was used as a negative control. Allcompounds were incubated with approximately 1-2 million cells/mL forvarying amounts of time to induce cell death and/or disrupt membraneintegrity. The compounds tested showed a gradient of cell membranedisruption and cell death as a function of time. All test compoundsinduced some degree of cell death that continued overnight. Fusedheterotricyclic organic compounds tested in the assay are shown in Table5 below, along with their compound identification number.

TABLE 5 Compound No. Chemical Structure II-1

II-2

II-3

II-4

II-5

II-6

II-7

Example 2 Evaluation of Adipocyte Cell Cytotoxicity for ExemplaryDipyrido-Pyrimidinone Organic Compounds

Exemplary dipyrido-pyrimidinone compounds of the invention wereevaluated for adipocyte cell cytotoxicity using a cellviability/cytotoxicity assay commercially available from MolecularProbes, located in Eugene Oreg.

Materials and Methods

Adipocytes were maintained using standard cell culture procedures.Approximately, 1-2 million cells/mL were incubated with either 10 or 15mg/mL of test compound or control at 37° C. for varying amounts of timeup to 24 hours. Following incubation with a test compound or control,aliquots of cells in solution were transferred to a 96-well microplateand prepared according to the manufacturer's instructions. Cells wereexposed to calcein AM and ethidium homodimer-1, each purchased fromMolecular Probes. Following incubation of the cells in presence ofcalcein AM and ethidium homodimer-1, the fluorescence signal of calceinand ethidium was then measured using a SpectraMax Multi-Mode MicroplateReader using optical filters and excitation and emission wavelengths of494 nm/517 nm and 528 nm/617 nm for calcein and ethidium bromide,respectively.

Results and Discussion

The time dependent effects of test compounds on both cell viability andcell toxicity were evaluated using a fluorescence assay that measuresplasma membrane integrity and intracellular enzyme activity. Briefly,live cells are determined by the increased fluorescence signal ofcalcein AM upon enzymatic conversion. In contrast, the ethidiumfluorescence signal is dramatically increased upon entering a cell withdamaged membranes and binding to nucleic acids. The ratio of ethidium tocalcein fluorescence can also be used to measure the relative amount oflive and dead cells. The ethidium signal was used as a measure of celldeath following the protocols outlined by the assay manufacturer. Testcompounds listed in Table 6 below were purchased from a commercialvendor.

The cell membrane disruption effects of various test compounds werecompared to the known cytotoxic compounds deoxycholic acid (DC), and thecombination of phosphatidylcholine and deoxycholic acid (PC/DC) (i.e.,as positive controls). Saline was used as a negative control. Allcompounds were incubated with approximately 1-2 million cells/mL forvarying amounts of time to induce cell death and/or disrupt membraneintegrity. The compounds tested showed a gradient of cell membranedisruption and cell death as a function of time. All tested contemplatedcompounds induced some degree of cell death that continued for at least24 hrs. However, at 10 mg/mL, the test compounds were initially lessaggressive than DC or PC/DC (FIG. 3 ). Increasing the concentration oftest compound to 15 mg/mL nonlinearly influenced the compound's cellkilling behavior (FIG. 4 ). Dipyrido-pyrimidinone organic compoundstested in the assay are shown in Table 6 below, along with theircompound identification number.

TABLE 6 Compound No. Chemical Structure II-1

II-2

II-3

Example 3 Evaluation of Adipocyte Cell Cytotoxicity for ExemplaryTetrahydropyrimido-Furo-Isoquinolinone Organic Compounds

Exemplary tetrahydropyrimido-furo-isoquinolinone compounds of theinvention were evaluated for adipocyte cell cytotoxicity using a cellviability/cytotoxicity assay commercially available from MolecularProbes, located in Eugene Oreg. Experimental procedures were analogousto those described in Example 1.

All test compounds were incubated with approximately 1-2 millioncells/mL for varying amounts of time to induce cell death and/or disruptmembrane integrity. The compounds tested showed a gradient of cellmembrane disruption and cell death as a function of time. All testedcompounds induced some degree of cell death that continued overnight(FIG. 5 ). Tetrahydropyrimido-furo-isoquinolinone organic compoundstested in the assay are shown in Table 7 below, along with theircompound identification number.

TABLE 7 Compound No. Chemical Structure II-1

II-2

II-3

Example 4 Evaluation of Adipocyte Cell Cytotoxicity for ExemplaryTetrahydrobenzo[4,5]Imidazo[1,2-a]Pyrazine Organic Compounds

Exemplary tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine compounds of theinvention were evaluated for adipocyte cell cytotoxicity using a cellviability/cytotoxicity assay commercially available from MolecularProbes, located in Eugene Oreg. Experimental procedures were analogousto those described in Example 1.

All test compounds were incubated with approximately 1-2 millioncells/mL for varying amounts of time to induce cell death and/or disruptmembrane integrity. The compounds tested showed a gradient of cellmembrane disruption and cell death as a function of time. Deoxycholicacid was the most aggressive cell killing compound tested, whichcorrelates with the highest ethidium signal over time. All testedcompounds induced some degree of cell death that continued overnight(FIG. 6 ). Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine organic compoundstested in the assay are shown in Table 8 below, along with theircompound identification number.

TABLE 8 Compound No. Chemical Structure II-1

II-2

II-3

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

1. A cosmetic method of modifying the contour of a subject's externallyexposed body part containing fat, the method comprising administering tosaid body part an amount of a compound of Formula I effective to modifythe contour of said body part, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,5-6 membered heteroaryl, aralkyl, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,hydroxyl, —(C₁-C₆)alkoxy, and —N(R⁵)R⁶; R² and R³ each representindependently for each occurrence hydrogen, —(C₁-C₆)alkyl, or halogen;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, —CO₂R⁶, —C(O)R⁶,—(C₁-C₆)alkylene-N(R⁵)R⁶, —(C₁-C₆)alkylene-OR⁶, or —(C₁-C₆)alkoxy; R⁵and R⁶ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached tothe same nitrogen atom, then R⁵ and R⁶ may be taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocycle; and n and m each represent independently 1 or
 2. 2. Themethod of claim 1, wherein the body part is the subject's face, neck,chin, submental region, arm, thigh, knee, calf, buttocks, hips, orabdomen.
 3. The method of claim 1, wherein the body part is thesubject's face.
 4. The method of claim 1, wherein the body part is thesubject's neck or submental region.
 5. The method of claim 1, whereinthe subject experiences at least a 5% by weight reduction in the amountof fat in the subject's body part exposed to said compound.
 6. Themethod of claim 1, wherein the subject experiences at least a 15% byweight reduction in the amount of fat in the subject's body part exposedto said compound.
 7. The method of claim 1, wherein the administeringcomprises injecting said compound into said body part.
 8. A methodselected from: (a) a method of reducing the amount of subcutaneous fatin a subject, comprising exposing subcutaneous fat in a subject to aneffective amount of a compound of Formula Ito reduce the amount ofsubcutaneous fat in said subject, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,5-6 membered heteroaryl, aralkyl, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,hydroxyl, —(C₁-C₆)alkoxy, and —N(R⁵)R⁶; R² and R³ each representindependently for each occurrence hydrogen, —(C₁-C₆)alkyl, or halogen;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, —CO₂R⁶, —C(O)R⁶,—(C₁-C₆)alkylene-N(R⁵)R⁶, —(C₁-C₆)alkylene-OR⁶, or —(C₁-C₆)alkoxy; R⁵and R⁶ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached tothe same nitrogen atom, then R⁵ and R⁶ may be taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocycle; and n and m each represent independently 1 or 2; b) amethod for inducing retraction of dermal tissue in a subject, comprisingadministering an effective amount of a compound of Formula Ito dermaltissue of a subject to induce retraction of dermal tissue, whereinFormula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,5-6 membered heteroaryl, aralkyl, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,hydroxyl, —(C₁-C₆)alkoxy, and —N(R⁵)R⁶; R² and R³ each representindependently for each occurrence hydrogen, —(C₁-C₆)alkyl, or halogen;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, —CO₂R⁶, —C(O)R⁶,—(C₁-C₆)alkylene-N(R⁵)R⁶, —(C₁-C₆)alkylene-OR⁶, or —(C₁-C₆)alkoxy; R⁵and R⁶ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached tothe same nitrogen atom, then R⁵ and R⁶ may be taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocycle; and n and m each represent independently 1 or 2; (c) amethod for inducing retraction of subcutaneous tissue in a subject,comprising administering an effective amount of a compound of FormulaIto subcutaneous tissue of a subject to induce retraction ofsubcutaneous tissue, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,5-6 membered heteroaryl, aralkyl, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,hydroxyl, —(C₁-C₆)alkoxy, and —N(R⁵)R⁶; R² and R³ each representindependently for each occurrence hydrogen, —(C₁-C₆)alkyl, or halogen;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, —CO₂R⁶, —C(O)R⁶,—(C₁-C₆)alkylene-N(R⁵)R⁶, —(C₁-C₆)alkylene-OR⁶, or —(C₁-C₆)alkoxy; R⁵and R⁶ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached tothe same nitrogen atom, then R⁵ and R⁶ may be taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocycle; and n and m each represent independently 1 or 2; (d) amethod of treating a disorder selected from the group consisting of anadipose tissue tumor, fat embolism, dyslipidemia, and or fatty liverdisease due to alcohol-induced liver cirrhosis in a subject, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of Formula I to treat the disorder, wherein FormulaI is represented by:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,5-6 membered heteroaryl, aralkyl, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,hydroxyl, —(C₁-C₆)alkoxy, and —N(R⁵)R⁶; R² and R³ each representindependently for each occurrence hydrogen, —(C₁-C₆)alkyl, or halogen;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, —CO₂R⁶, —C(O)R⁶,—(C₁-C₆)alkylene-N(R⁵)R⁶, —(C₁-C₆)alkylene-OR⁶, or —(C₁-C₆)alkoxy; R⁵and R⁶ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached tothe same nitrogen atom, then R⁵ and R⁶ may be taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocycle; and n and m each represent independently 1 or 2; (e) amethod of reducing the amount of fat or cholesterol in a subject,comprising administering to a subject in need thereof an effectiveamount of a compound of Formula I to reduce the amount of fat orcholesterol in the subject, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,5-6 membered heteroaryl, aralkyl, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,hydroxyl, —(C₁-C₆)alkoxy, and —N(R⁵)R⁶; R² and R³ each representindependently for each occurrence hydrogen, —(C₁-C₆)alkyl, or halogen;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, —CO₂R⁶, —C(O)R⁶,—(C₁-C₆)alkylene-N(R⁵)R⁶, —(C₁-C₆)alkylene-OR⁶, or —(C₁-C₆)alkoxy; R⁵and R⁶ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached tothe same nitrogen atom, then R⁵ and R⁶ may be taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocycle; and n and m each represent independently 1 or 2; and (f) amethod of reducing the amount of mesenchymal pre-adipocyte stem cellprecursors in a subject, comprising administering to a subject in needthereof an effective amount of a compound of Formula I to reduce theamount of mesenchymal pre-adipocyte stem cell precursors in the subject,wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,5-6 membered heteroaryl, aralkyl, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,hydroxyl, —(C₁-C₆)alkoxy, and —N(R⁵)R⁶; R² and R³ each representindependently for each occurrence hydrogen, —(C₁-C₆)alkyl, or halogen;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, —CO₂R⁶, —C(O)R⁶,—(C₁-C₆)alkylene-N(R⁵)R⁶, —(C₁-C₆)alkylene-OR⁶, or —(C₁-C₆)alkoxy; R⁵and R⁶ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached tothe same nitrogen atom, then R⁵ and R⁶ may be taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocycle; and n and m each represent independently 1 or
 2. 9. Themethod of claim 1, wherein the subject is an adult human.
 10. The methodof claim 1, wherein R⁴ is —C(O)NH₂.
 11. The method of claim 10, whereinR¹ is (i) phenyl substituted with a methoxy group and optionally 1 or 2additional substituents independently selected from the group consistingof halogen and —(C₁-C₆)alkyl, or (ii) R¹—(C₁-C₆)alkylene-OH.
 12. Themethod of claim 1, wherein the compound is represented by Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen,—(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, hydroxyl, and —(C₁-C₆)alkoxy; R² andR³ each represent independently for each occurrence hydrogen and methyl;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, or —(C₁-C₂)alkylene-N(R⁵)R⁶; and R⁵and R⁶ each represent independently hydrogen, —(C₁-C₆)alkyl, or—(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached to the same nitrogenatom, then R⁵ and R⁶ may be taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocycle.
 13. Themethod of claim 1, wherein the compound is a compound in Table 4 hereinor a pharmaceutically acceptable salt thereof.
 14. The method of claim1, wherein the compound is one of the following or a pharmaceuticallyacceptable salt thereof:


15. The method of claim 2, wherein the compound is represented byFormula I-A:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen,—(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, hydroxyl, and —(C₁-C₆)alkoxy; R² andR³ each represent independently for each occurrence hydrogen and methyl;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, or —(C₁-C₂)alkylene-N(R⁵)R⁶; and R⁵and R⁶ each represent independently hydrogen, —(C₁-C₆)alkyl, or—(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached to the same nitrogenatom, then R⁵ and R⁶ may be taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocycle.
 16. Themethod of claim 2, wherein the compound is a compound in Table 4 hereinor a pharmaceutically acceptable salt thereof.
 17. The method of claim2, wherein the compound is one of the following or a pharmaceuticallyacceptable salt thereof:


18. The method of claim 8, wherein the compound is represented byFormula I-A:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from the group consisting of halogen,—(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl, hydroxyl, and —(C₁-C₆)alkoxy; R² andR³ each represent independently for each occurrence hydrogen and methyl;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, or —(C₁-C₂)alkylene-N(R⁵)R⁶; and R⁵and R⁶ each represent independently hydrogen, —(C₁-C₆)alkyl, or—(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached to the same nitrogenatom, then R⁵ and R⁶ may be taken together with the nitrogen atom towhich they are attached to form a 3-7 membered heterocycle.
 19. Themethod of claim 8, wherein the compound is a compound in Table 4 hereinor a pharmaceutically acceptable salt thereof.
 20. The method of claim8, wherein the compound is one of the following or a pharmaceuticallyacceptable salt thereof:


21. A pharmaceutical composition, comprising a compound of Formula I anda pharmaceutically acceptable carrier, wherein Formula I is representedby:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenyl,5-6 membered heteroaryl, aralkyl, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl—(C₁-C₆)alkylene-OH, or —(C₁-C₆)alkylene-O—(C₁-C₆)alkyl, wherein saidphenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionallysubstituted with 1, 2, or 3 substituents independently selected from thegroup consisting of halogen, —(C₁-C₆)alkyl, —(C₃-C₆)cycloalkyl,hydroxyl, —(C₁-C₆)alkoxy, and —N(R⁵)R⁶; R² and R³ each representindependently for each occurrence hydrogen, —(C₁-C₆)alkyl, or halogen;R⁴ is —C(O)N(R⁵)R⁶, —N(R⁵)C(O)R⁶, —CO₂R⁶, —C(O)R⁶,—(C₁-C₆)alkylene-N(R⁵)R⁶, —(C₁-C₆)alkylene-OR⁶, or —(C₁-C₆)alkoxy; R⁵and R⁶ each represent independently for each occurrence hydrogen,—(C₁-C₆)alkyl, or —(C₃-C₆)cycloalkyl; or when R⁵ and R⁶ are attached tothe same nitrogen atom, then R⁵ and R⁶ may be taken together with thenitrogen atom to which they are attached to form a 3-7 memberedheterocycle; and n and m each represent independently 1 or
 2. 22. Thepharmaceutical composition of claim 21, wherein the compound is acompound in Table 4 herein or a pharmaceutically acceptable saltthereof.